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The ethics of creating human embryos for research for the

responsible introduction of artificial gametes in clinical practice

Student: Verna Jans (s1622536)

Track: Technology and Values

Date: August 22nd, 2016

First Supervisor: Dr. S.K. Nagel

Second Supervisor: Dr. W. Dondorp

Examiner: Dr. M. Boenink

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An emerging technique in the field of assisted reproductive technologies is the use of stem-cell-

derived (SCD) gametes. In the future, this technique may be used as a fertility treatment for those

presently dependent on reproduction using donor gametes. History shows that all too often,

assisted reproductive technologies are introduced into clinical practice on a trial and error basis.

Therefore, the possible introduction of SCD gametes in medically assisted reproduction raises the

question how, for this technology, the step to the clinic can be made responsibly. One element of

improving assisted reproductive technology research is to systematically perform preclinical

human embryo research (under the condition that it can provide additional safety information that

would reduce the gap between animal studies and the first use of a new technology in humans).

While some assisted reproductive technologies can be investigated using leftover embryos after

IVF procedures, research on stem-cell-derived gametes can only be performed with specifically

created research embryos. However, the creation of human embryos for research is regarded as

morally problematic because of concerns on the moral status or value of human embryos, and/or

to the risk that women will be pressured into donating oocytes against their best interest. This

thesis answers the question if and how the creation of human embryos for safety research can be

ethically justified, in particular in safety research concerning the responsible introduction of SCD

gametes in clinical practice Using the method of wide reflective equilibrium, I argue that the

creation of embryos for research can be justified, if the requirements of the principles of

proportionality (meaning the research has a morally important aim) and subsidiarity (meaning the

research cannot be performed with less invasive means) are met. My stance is that this is the case

in embryo research concerning the responsible introduction of SCD gametes into clinical

practice. Therefore, my conclusion is that the creation of human embryos for safety research

concerning the responsible introduction of SCD gametes in clinical practice can be justified.

Keywords: ethics, embryo research, assisted reproductive technology, artificial gametes, stem-

cell-derived gametes

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Chapter 1: introduction …………………………………………………………………………………………………………………….11

1.1. SCD Gametes …………………………..…………………………………………………………………………………………………………….11

1.2. Background of the problem……………….…………………………………………………………………………………………………..12

1.3. Embryo research as a possible element of safety research…………………………………………………………………….13

1.3.1. The ethics of embryo research ..……………………………………….………..…………………………………………………………14

1.3.2. The ethics of creating embryos for research ..……………………………………………………………………………………….15

1.3.3. The ethics of donor egg cells …………..……………………………………………………………………………………………………15

1.4. Embryo research on SCD gametes …………………………………….……………………………………………………………………16

1.5. Roadmap …………..……………………………………………………………………………………………………………………………………16

1.6. Method …………..……………………………………………………………………………………………………………………………………..17

1.6.1. literature research ..……………………………………………………………………………………………………………………………..17

1.6.2. Wide Reflective Equilibrium ………………………………………………………………………………………………………………….17

Chapter 2: Assisted reproductive technology and Safety Research………………..…….21

2.1. The lack of safety research on ARTs in today's clinical practice …………………………………………………………….21

2.1.1. In Vitro Fertilization ……………………………………………………………………………………………………………………………..21

2.1.2. Intracytoplasmic Sperm Injection …………………………………………………………………………………………………………23

2.1.3. Mitochondrial Supplementation/ Augment treatment ……………………….…………………………………………….....25

2.2. Recommendations ………………………………………..……………………………………………………………………………………….27

2.2.1. ESHRE ………………………………………………………………………………………………………………………………………………....28

2.2.2. ACOG …………………………………………………………………………………………………………………………………………….…….29

2.2.3. ASRM …………………………………………………………………………………………………………………………………………………..30

2.3. Recommendations in practice ……………………………………………..………………………………………………………………..30

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Chapter 3: Stem-Cell Derived Gametes…………………………………………………………….....33

3.1. Envisaged applications of SCD gametes …………………………………………………………………….…………………...…….33

3.2. Current state of research ……………………………………………………………………………………………………………………….36

3.2.1. Embryonic Stem Cells ……………………………………………………………………………………………………………………….….36

3.2.2. Induced Pluripotent Stem Cells …………………………………………………………………………………………………………….38

3.3. Utility of Preclinical Safety Studies Using Human Embryos …………………………………………………………………..39

3.3.1. Systematic Formal Research ………………………………………………………………………………………………………………..39

3.3.2. Preclinical Embryo Research ………………………………………………………………………………………………………………..40

3.3.3. The Creation of Embryos for Research …………………………………………………………………………………………………41

Chapter 4: The Ethics of Embryo Research……………………………………………………………………………….43

4.1. Ethical Perspectives on Embryo Research ………………………………………….………………………………………………….44

4.1.1. The moral status of the embryo is the same as the moral status of a born human individual ..........….….45

4.1.2. Embryos have symbolic worth at best ………………………………………………………….………………………………………46

4.1.3. Embryos have a limited worth of protection…………………………………………………………………….……………………47

4.2. Ethical perspectives on creating embryos for research ………………..…………………………………………….…………48

4.2.1. Inherent moral status …………………………………………………………………………………………………………………..………49

4.2.2. Intention ………………………………………………………………………………………………………………………………………………50

4.3. Ethical Perspectives on obtaining donor egg cells ……………………………..………………………………………….………55

4.3.1. Risks and benefits …………………………………………………………………………………………………………………..……………55

4.3.2. Coercion and exploitation ………………………………………………………………………………………………………….…………56

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Chapter 5: Can the Creation of Embryos for Safety Research on SCD Gametes be

Justified? …………………………………………………………………………………………………………….59

5.1. Wide reflective equilibrium …………………………………………………………………………………………………………..………59

5.2. Acceptability of the use and creation of embryos for research ………………………………………….…………………61

5.2.1. A matter of moral status: personhood & potentiality ……………………………………………………………………..……61

5.2.2. The justifiability of embryo research ……………………………………………………………..…………………………………….66

5.2.3. A matter of double effect and instrumental value ………………………………………………………….……………….……68

5.2.4. The justifiability of creating embryos for research …………………………….…………………………………………………72

5.2.5. the ethics of obtaining egg cells to create embryos for research …………………………………………………….……78

5.2.6. Subsidiarity and proportionality …………………………………………………………………………………………………………..79

5.3. The case study: SCD Gametes ………………………………………………………………………………………………………………..80

5.3.1. Subsidiarity ………………………………………………………………………………………………………………………………………….81

5.3.2. Proportionality …………………………………………………………………………………………………………………………………….82

Chapter 6: Conclusion …………………………………………………………..……………………………………………………………85

6.1. Results ………………..…………………………………………………………………………………………………………………….……………85

6.2. Strengths and limitations ………………………………………………………………….…………………………………………………..90

6.3. Recommendations ………………………………………………..…………………………………………………………………………….…91

Literature .………………………………………………………………………………………………………………………………………..………93

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1.1. SCD Gametes

Current stem cell research suggests that it may be possible in the future to create eggs and sperm

from human pluripotent stem cells (K. Hayashi et al., 2012; K. Hayashi, Ohta, Kurimoto,

Aramaki, & Saitou, 2011; Katsuhiko Hayashi & Saitou, 2013; Marques-Mari, Lacham-Kaplan,

Medrano, Pellicer, & Simón, 2009). These new cells are called Stem-Cell-Derived (SCD)

gametes, otherwise referred to as artificial gametes. In contrast to what ‘artificial’ might suggest,

these gametes are completely made out of natural body tissue. For example, gametes can be

created out of skin cells. The ‘artificial’ element in this case, refers to the action of differentiating

pluripotent stem cells to gametes.

As a new assisted reproductive technology (ART), the use of these SCD gametes would

make it possible to treat several forms of infertility and would thus make donor conception

redundant. To give an example, from e.g. skin cells, taken from an infertile man, pluripotent stem

cells could be made, which could in turn be differentiated into sperm cells and thereafter used to

fertilize an egg cell of his partner. In contrast to conception with the use of donor gametes, the

conceived child would be genetically related to both parents.

Additionally, if some serious issues could be overcome, it could give same-sex couples a

method to create children of which they are both a biological parent. This would mean that, for

example, in a case of an all-male couple, an SCD egg cell can be created from a pluripotent cell

from one of the men. The SCD gamete will thereafter be used to fertilize the naturally conceived

sperm cell from the other man. However, this is more complicated then with heterosexual

couples, because the derivation of oocytes from an XY stem line or even more problematic;

sperm from an XX stem line, is more likely to have chromosomal problems than derivation of a

sex cell from the same sex (de Sutter et al., 2015).

Although the development of SCD gametes is still at a research stage, current research

suggests medically assisted reproduction using SCD-gametes is a possible scenario (particularly

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for heterosexual couples) in the near to midterm future (Hendriks, Dancet, van Pelt, Hamer, &

Repping, 2015). This raises the question if and how SCD gametes should be safely introduced in

clinical practice. This thesis will focus on one element of safety research on SCD gametes;

embryo research. The main question will be if and how the creation of human embryos1 for safety

research can be ethically justified, in particular in safety research concerning the responsible

introduction of SCD gametes in clinical practice.

1.2. Background of the problem

Several authors have pointed out that all too often, the introduction of new ARTs has in the past

taken place on a trial and error basis (Dondorp & de Wert, 2011; Harper, Magli, Lundin, Barratt,

& Brison, 2012; Provoost et al., 2014; Van Steirteghem, 2008). According to André van

Steirteghem, Editor-in-chief of Human Reproduction, “the recent history of reproductive

medicine indicates that very few, if any, new developments have been introduced into clinical

practice after thorough and rigorous clinical validation” (Van Steirteghem, 2008). Examples of

innovations that have been introduced in clinical practice without much preclinical research into

their effectiveness and safety are cryopreservation of embryos, ICSI, ooplasm transfer and most

recently oocyte vitrification (Dondorp & de Wert, 2011). Also, in the light of the health interests

of children conceived through these technologies, more research has to be performed on the

possible health impacts of new reproductive technologies before they are made available for

patients (Dondorp & de Wert, 2011; Pennings et al., 2007).

Similarly, Joyce Harper, expert on human genetics and embryology, argued that there are

many ARTs that have been introduced in clinical practice without sufficient safety research

(Harper et al., 2012). In the case of IVF for example, “developments of IVF treatments are often

both money and patient-driven and the necessary research is not conducted or is conducted after

the procedure has been introduced into the clinical setting” (Harper et al., 2012, p. 305). Also,

“the introduction of ICSI was a revolution in reproductive medicine but was introduced into

clinical practice without any proof of safety” (Harper et al., 2012, p. 309).

Apparently, the introduction of ARTs in clinical practice often lacks (sufficient) research

on their effectiveness and safety. Therefore, ART research should be improved. Although there

are several good recommendations to improve research on the effectiveness and safety of ARTs

1 For economy’s sake I use the term ‘embryo’ as a shorthand for ‘human embryo’ throughout this thesis

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(ACOG, 2006a; ASRM, 2014; Pennings et al., 2007), these are most of the time not followed in

practice. This can have various reasons, such as patients pressuring to introduce the treatment, the

desire to receive money from patients at the earliest convenience, or ethical and legal issues

withholding research. Without appropriate safety and effectiveness research it would be

irresponsible towards patens and potential children to introduce new ARTs. This means that also

safety and effectiveness research for the responsible introduction for SCD gametes into clinical

practice needs improvement.

1.3. Embryo research as a possible element of safety research

European Society of Human Reproduction and Embryology (ESHRE) suggests that appropriate

ART research would have to consists out of a threefold of steps (Pennings et al., 2007). It needs

to start with preclinical research in animal models, then to use human preimplantation embryos

for additional research and last to make sure that clinical studies are performed with collecting

sufficient data about effectiveness and safety (Dondorp & de Wert, 2011). This thesis will focus

on the second step; embryo research.

Embryo research can be the step between animal studies and actually using SCD gametes

in clinical practice, which would decrease the yet unknown safety risks for patients in clinical

practice (Dondorp & de Wert, 2011; Hinxton, 2008; Pennings et al., 2007). Of course, inserting

embryo research as a step in the chain of safety procedures is only a good idea when it is

expected that it would actually contribute relevant and useful information on the safety of the

technology. In a consensus statement, scientists working on the development of SCD gametes

have suggested that such preclinical safety studies using embryos would indeed be an important

condition for the responsible introduction of this new technology (Hinxton, 2008). To perform

such research on embryos, would mean that instead of transferring the SCD embryos to the

womb of a woman, they would be subjected to research. All cells will be taken apart to analyze

several biological processes, like mitoses and several forms of (epi-)genetic expression which are

relevant for the normal development of the embryo. Subjecting the embryos to research would

thus mean to destroy them.

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1.3.1. The ethics of embryo research

Although research has argued that using embryos for safety research can be of significant

importance, it nevertheless leads to several ethical issues. The first issue questions if the use of

embryos for research is actually acceptable. Because the benefit of performing safety research

should be balanced against the harm of using embryos, it is key to define the moral status of the

embryo. To define the moral status of the embryo is important, because the higher the moral

status of an embryo is considered, the greater the benefits that would be necessary to justify the

use of the embryo.

The Health Council of the Netherlands identified three views considering the moral status

of the embryo (Gezondheidsraad, 1998, p. 60). According to the first view, the moral status of the

embryo is the same as the moral status of a grown human being. Therefore, embryos should be

protected at the same level as grown human beings should be protected (Gezondheidsraad, 1998,

pp. 60-61). Another view argues that embryos do not have a moral status on which ground they

should be protected. They should not be treated any differently than the gametes from which they

derive. A third view considers embryos to have a limited worth of protection. This view does not

consider the embryo a human being, but still thinks that there can be granted moral relevance

because the embryo can grow into a human being. Thus, the embryo does have a moral status,

however this status is not equal to the moral status of a grown human. Often, it is added that the

worth of protection increases the more the embryo develops (Gezondheidsraad, 1998, pp. 61-62).

Following this view, it can be argued that embryo research can be justified if the research (and

the way of conducting the research) is commensurable with the embryo’s limited moral status.

There is a lack of consensus on the acceptability of embryo research at European level

(ESHRE, 2001). It has been suggested that the beliefs on the moral status of the embryo and

embryo research are often shaped by several cultural traditions, such as scientific advances in

biology and medicine, and especially by religion (Pardo & Calvo, 2008). However, several

commentators argue that there is actually a broad consensus on the relatively low moral status of

the embryo, because the justification of IVF in many European countries presupposes such a

limited moral status (Devolder, 2005; Dondorp & de Wert, 2007).

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1.3.2. The ethics of creating embryos for research

If embryo research would be considered acceptable, would it also be justifiable to create embryos

for the purpose of research? Currently, in most countries in Europe, including the Netherlands2,

the creation of embryos for research is not allowed. The use of spare embryos (leftover embryos

after IVF treatment) is in most countries authorized. However, for safety research on SCD

gametes, the creation of embryos is necessary. The safety of using SCD gametes can only be

investigated in embryos developed by using SCD gametes. This means that safety research

cannot use spare embryos that stem from IVF, and that will therefore not be made using SCD

gametes. If embryo research is argued for to be a contribution to safety, then what are the

arguments for prohibiting it? Moreover, do the moral arguments behind the legal prohibition

weigh up against the predicted improvement of safety research?

I argue that the moral debate on the creation of embryos for research focuses on whether a

moral difference can be made between using spare embryos for research and creating research

embryos. If there is no moral difference between using spare and creating research embryos, it

could be argued that the creation of research embryos should be allowed just like the use of spare

embryos is. This issue has been a longstanding topic of debate in the field of embryo research,

whereby one position uses the distinction to defend the prohibition on research embryos

(FitzPatrick, 2003; Murphy, 2012; van Beers, 2016), while others argues that such moral

distinction is invalid (Brock, 2010; Devolder, 2005, 2013).

1.3.3. The ethics of donor egg cells

The creation of embryos does not only cause ethical issues concerning embryos, but also

concerning women. To create embryos for research, a great amount of gametes is needed. Sperm

cells are relatively easy to acquire, but egg cells are much more difficult to obtain. Several

authors have argued that the need for oocyte donors can increase the risk of coercion and

exploitation of women, since oocyte donors have to undergo hormone therapy and an invasive

IVF procedure without receiving any physical, personal or financial benefits (Baylis, 2000;

Gerrand, 1993). Moreover, the need for egg donation can threat women´s autonomy (Gerrand,

2 However, Dutch Minister Schippers has recently suggested, in reaction to the Pallas report (Eeuwijk, Kochems, van

den Bosch, & Smilde-van den Doel, 2015), to broaden the current embryo law. This means that the creation of

embryos for ‘very important ’research purposes would be allowed in The Netherlands. An example of such ‘very

important’ research, would be specific research concerning infertility, assisted reproductive technologies and

hereditary or congenital disorders (Schippers, 2016).

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1993). Because the long-term effects of IVF are not fully understood yet, it is impossible for

women to make a fully informed choice about egg donation (Brison, Roberts, & Kimber, 2013;

Gerrand, 1993).

Additionally, it has been argued that ARTs can cause several social concerns, such as the

possibility that women would be perceived as just reproductive vessels (Arditti, Klein, &

Minden, 1984; Corea, 1985; Rowland, 1992). When women are used for harvesting eggs in order

to create embryos for research, this could lead to exploitation of women (Dickenson, 2002;

Gerrand, 1993)

1.4. Embryo research on SCD gametes

Although it is argued that embryo research is important in the responsible introduction of SCD

gametes in clinical practice (De Rycke, Liebaers, & Van Steirteghem, 2002; Eeuwijk et al., 2015;

Gezondheidsraad, 1998; Hinxton, 2008; ZonMw, 2012) literature on the moral justification of

embryo research on SCD gametes in specific is lacking. Under the condition that embryo

research is useful and the creation of embryos is acceptable for safety research on several ARTs,

can the creation of embryos also be justified for the purpose of safety research on SCD gametes?

Therefore, the possible justification of research embryos for the purpose of safety research on

SCD gametes in specific should be investigated.

Two conditions under which the creation of embryos for research on artificial gametes

could be justified are proportionality and subsidiarity (Isasi & Knoppers, 2006). To meet the

proportionality condition would mean that the importance of the development of SCD gametes

and the profit of embryo research weights up against the harm involved in the destruction of

embryos. To meet the subsidiarity principle, it would mean that the knowledge that embryo

research would provide cannot be performed with spare embryos or other research methods.

1.5. Roadmap

This thesis will investigate the ethical arguments that are made regarding the creation of embryos

for research. The main research question will be if the creation of embryos for safety research can

be ethically justified, in particular in safety research concerning the responsible introduction of

SCD gametes in clinical practice. I will start with examining the current research in the ART

field. It will be argued that there are shortcomings considering the safety of introducing ARTs in

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clinical practice. Second, I will examine SCD gametes and its safety research. An introduction on

SCD gametes will be given. I will investigate its safety research and examine what embryo

research on artificial gametes would mean and why it is recommended. Thereafter, the ethical

perspectives on embryo research will be analyzed. I will first briefly analyze the current moral

perspectives on embryo research. After that, I will focus on the arguments considering the

distinction between spare embryos and research embryos. Then, the moral implications of egg

cell donation will be investigated. In the following chapter, the arguments on embryo research in

general will be assessed and consequently be applied to SCD gametes in specific. The aim is to

examine if the creation of research embryos for safety research on SCD gametes can be justified.

1.6. Method

1.6.1. Literature Research

For this thesis, English and Dutch journal articles have been selected, the majority of which is

published in the last twenty years. This thesis aims to perform a normative ethical assessment in

the field of ART and embryo research. Therefore, literature is chosen from mainly scientific

journals focusing on normative aspects of biotechnology, ARTs and embryo research. This

means that alternative approaches to examine the justifiability of embryo research have not been

taken into account extensively. For example, approaches concerning the effect of social, political

and cultural values on technological innovation and their effect on society, politics and culture

are not widely expanded.

1.6.2. Wide Reflective Equilibrium

To investigate the possible justification of embryo research on artificial gametes, I will make use

of Wide Reflective Equilibrium (WRE) (Daniels, 1979, 2011; Rawls, 1971). This procedural

ethical approach (and at the same time a theory) is developed by John Rawls (Rawls, 1971) and

later interpreted by Norman Daniels (Daniels, 1979, 2011). In Rawls’ A theory of Justice (Rawls,

1971), Rawls proposes that we can only determine what principles of justice we should adopt by

broadening our circle of beliefs, on condition that this circle is coherent. This means that WRE

does not take an extreme position or gives authority to certain moral theories or empirical data,

but includes a wide range of moral theories and empirical data in order to reach a normative

conclusion (Molewijk, Stiggelbout, Otten, Dupuis, & Kievit, 2004). Rawls argues that we should

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include intuitions, normative frameworks and background theories in the assessment. Examples

of such theories, or crucial beliefs, concern the nature of persons, psychology or beliefs about

justice (Daniels, 2011). In later work from Rawls, he emphasizes that WRE is not an account of

truth, but only of justification (Rawls, 1993).

The advantage of using WRE is that it enables me to evaluate moral judgements in a

broader field of moral principles and background theories on embryo research (Daniels, 2011).

By including a broad range of considerations, WRE distinguishes itself from more foundationalist

approaches, such as consequentialist ethics and deontology, which only focus on a narrow range

of particular cases and moral principles. With ‘foundationalist’, I mean that such approaches are

based on an account of morality as rooted in what are claimed to be universally valid rules, or in

a universally valid understanding of the meaning of moral terms (e.g. categorical imperative,

hedons over dolors, etc.). In contrary to WRE, foundationalist approaches do not take practice-

based principles and intuitions into account, which leads to an ethical assessment distancing itself

from current practice. Since the described ethical debate on embryo research is so closely

connected to scientific and medical practice, it is important to take all (practice-based)

considerations into account. Therefore, WRE is a better fit to the ethical assessment of this thesis

than the rather narrow foundationalist approaches. WRE makes it is possible to include all

possible moral theories in the assessment without leaving important elements out. This means

that e.g. the moral value of the embryo and theories on personhood as well as the consequences

of safety research are part of the evaluation.

Furthermore, the outcome of the procedure of WRE is in all cases fair to all parties,

because it is the result of a procedure of which the considerations of all parties have been taken

into account (Rawls, 1971, p. 104; 1993, p. 72). Instead of evaluating ethical issues in terms of a

foundationalist framework, WRE examines the consistency of ethical arguments within the

overall ´equilibrium´ of intuitions and theories and supplements arguments with general practice-

based principles and intuitions. It is important that the considerations of all relevant actors are

involved, which is called the inclusiveness criterion (Doorn, 2011, p. 76). Since the

considerations of all parties are included in the ethical assessment, the result of the WRE

procedure is fair to all parties. This is called pure procedural justice: “what is just is specified by

the outcome of the procedure, whatever that is” (Doorn, 2011, p. 70). WRE is therefore ideal to

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reach moral agreement between various parties in ethical diverging debates such as the debate I

identified on embryo research.

Additionally, by using WRE, it is possible to distinguish moral disagreements from

disagreements resting on non-moral disagreements, such as background theories. Disagreements

about background theories are more tractable than disagreements about moral judgements or

principles (Daniels, 1979). For example, the moral disagreements concerning the use of embryos

for research rest on several background theories, such as theories concerning personhood and

potentiality. WRE enables us to understand the reasons behind considerations in people’s

arguments (Daniels, 1979).

The WRE assessment of this thesis will include considerations on research embryos in

general as well as on the supposed distinction between spare embryos and research embryos and

the moral concerns on oocyte donation. In chapter four, I will first study different ethical

perspectives on embryo research and discuss their adequacy to deliberate ethical questions on the

creation of embryos for safety research. These views include the moral status of the embryo and

the difference it makes to evaluating if embryos could be used for safety research. Furthermore,

the difference between using spare embryos and the creation of embryos for research will be

examined. Additionally, I will study the moral implications of egg cell donation, focusing on the

risk of exploitation of women. In chapter five, I will first explain the procedural method of WRE.

Thereafter, I will apply WRE to assess the arguments on the creation of embryos for research, in

particular on SCD gametes, by evaluating their consistency with the broader ethical intuitions,

principles and theories that I will examine. In addition to considering the ethical acceptability

both of embryo research as such and of the creation of embryos for research, I will focus on the

principles of proportionality and subsidiarity, because they enable me to evaluate if embryo

research can be justified on SCD gametes research in particular.

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Many ARTs are introduced into clinical practice without sufficient safety research. Several

authors have pointed out that all too often, the introduction of new ARTs has in the past taken

place on a trial and error basis (Brison et al., 2013; Dondorp & de Wert, 2011; Harper et al.,

2012; Pennings et al., 2007; Provoost et al., 2014; Van Steirteghem, 2008). This means that the

research that is necessary to examine the safety of a technology is often not performed before

introducing it into clinical practice.

In the light of the health interests of children conceived through these technologies, as

well as of the health interests for the parents, current safety research should be improved. Pointed

out by the European Society of Human Reproduction and embryology (ESHRE), “Technology

and research must always be subordinate to the welfare of the future offspring” (Pennings et al.,

2007, p. 2587). Sadly, history shows that new ARTs were (and are) regularly introduced without

such subordination. Therefore, in this chapter, I will first investigate three examples of ART

safety research. Thereafter, I will examine what the current recommendations on ART innovation

are, and last, I will show that these recommendations are generally not followed in practice.

2.1. The lack of safety research on ARTs in today’s clinical practice

2.1.1. In Vitro Fertilization

One of the ARTs that are used in clinical practice is in vitro fertilization (IVF). IVF is a

procedure where the egg cell of a woman is fertilized by a sperm cell outside the woman’s body.

In Vitro, which means “in glass”, refers to the early biological experiments that were performed

in glass containers, like petri dishes or test tubes. Nowadays, it refers to any biological procedure

that is performed outside the organic body, which originally occurs inside the organic body. The

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treatment is often used when women cannot (easily) get pregnant. This has several possible

causes, such as hormonal dysfunctions or closed or removed oviducts of the woman, or

deviations in the production or ejaculation of the sperm of the man.

In IVF procedures, one egg cell and multiple sperm cells are brought together in a

laboratory, completely outside the body. The procedure consists of several steps. First, the

woman is given fertility drugs to increase her egg production. Whereas a woman normally

produces one egg a month, these drugs enable her to produce several eggs. Thereafter, all of the

women’s eggs are removed from their ovary with a long, thin needle. Then, the eggs with the best

quality are brought together with sperm cells in the laboratory to allow the fertilization process to

start. The ensuing embryo development will be monitored for several days. After successful

fertilization the resulting zygote starts a process of cell division. Three or five days later, the

resulting embryos will be selected for transfer to the uterus of the woman. If an embryo implants

in the lining of the womb of a woman and grows, this results in pregnancy. Unless a priori

chances that the procedure will lead to a child are low, only one embryo is placed into the womb

of the woman at the same time. This policy aims to reduce the risk of twins and to avoid higher

multiples as much as possible, given that multiple pregnancies have a higher rate of

complications and outcomes (such as preterm birth, low birthweight) that may also affect the long

term health of the child. Good quality embryos that are not used in the same cycle may be frozen

for use in a next attempt or for donation, either to other infertile couples or to scientific research

(Goldberg, Falcone, & Attaran, 2007).

In the mid-seventies, when IVF was not yet successfully used in humans, it was proposed

that the safety of IVF methods should first be sufficiently verified in monkeys before exposing it

to women (Dondorp & de Wert, 2011, p. 2). Despite this recommendation, those working on the

technology thought that such research would be too expensive and time consuming. John

Biggers, who made a great contribution with mouse research on IVF, said during an interview on

an early debate on possible funding of clinical IVF: “I knew enough about working with monkey

embryos to state that the order of fifty years would be needed to get these answers using

monkeys, as well as the need of enormous expenditure of research money. I felt that we already

had enough information to proceed with caution”(Summers & Racowsky, 2008).

Some years earlier, in 1971, Cambridge physiologist Robert Edwards and Oldham

gynecologist Patrick Steptoe applied for long-term funding from the British Medical Research

23

Council (MRC) for a program of scientific and clinical ‘Studies on Human Reproduction’. Their

application was rejected because the MRC did not consider infertility high priority and set the bar

for safety very high (Johnson, Franklin, Cottingham, & Hopwood, 2010). Alternative funding

came from private donors leading to further experimentation as a result of which in 1978 the first

IVF baby, Louise Brown, was born. Instead of performing systematic research like the rejected

application aimed at, the research was rather performed as innovative treatment (Dondorp & de

Wert, 2011, p. 3). After the birth of Louise Brown and another healthy baby, the MRC changed

its viewpoint and started to support IVF enthusiastically (Johnson et al., 2010).

Both cases describe the trial and error introduction of IVF and seem to support the view

of Joyce Harper, who argues that “developments of IVF treatments are often both money and

patient-driven and the necessary research is not conducted or is conducted after the procedure has

been introduced into the clinical setting” (Harper et al., 2012, p. 305). As shown in the first

example, additional safety research was considered ‘too expensive’ and ‘too time-consuming’.

Therefore, research was mainly performed with mouse models. Jason Biggers declined the

recommendation to perform monkey research for these reasons. In the second example, the MRC

first supported a high standard for safety research and therefore declined the application of

Edwards and Steptoe. However, when the project continued with private funding and two patients

were given healthy babies, the council suddenly started to support IVF. In both cases, the safety

research that some considered necessary was not performed before introducing IVF as a

treatment.

2.1.2. Intracytoplasmic Sperm Injection

Another ART used in clinical practice is intracytoplasmic sperm injection (ICSI). ICSI is an

assisted reproductive method whereby one sperm cell is directly injected into an egg cell. The

treatment was first used in cases of severe male infertility where the sperm is of low quality

and/or quantity. The procedure is also used in cases where IVF is combined with preimplantation

genetic diagnosis (PGD) and in many centers worldwide more generally as a substitute for

classical IVF.

Technically, ICSI is an addition to the normal IVF treatment. Instead of bringing eggs and

sperm together, one sperm cell is ejected into one egg cell in vitro. A normally build, moving

sperm cell is isolated and its tail is made immotile. The egg cells are also investigated with a

24

microscope and their cumulus cells (collection of cells around a mature egg cell) are removed.

After preparing both gametes, the sperm cell is injected in the egg cell.

An early form of ICSI was developed in 1962, where sea urchin sperm was microinjected

into sea urchin eggs by a research team led by Hiramoto (Hiramoto, 1962). In the 1970s and

1980s, this method was developed in rodents. However, in rodents as well as in larger animals

such as the bovine later on, it resulted in a low pregnancy rate (Goto, 1993; Keefer, 1989;

Thadani, 1979). Despite these low pregnancy rates in animal models, a similar technique,

subzonal injection (SUZI), was discovered by research in humans. Although SUZI led to a

human pregnancy in 1988 (S. C. Ng et al., 1988), the technique was very quickly replaced by a

more promising treatment: ICSI. ICSI was applied in humans in 1988, which resulted in the first

reported human ICSI pregnancy in 1992 (Lanzendorf et al., 1988; Palermo, Joris, Devroey, &

Van Steirteghem, 1992). Thereafter, the majority of fertility centers adopted ICSI (Harper et al.,

2012, p. 305). ICSI can be performed in three different forms. The first form is as we use ICSI

regularly today, by injecting ejaculated sperm into an egg cell. The other two forms, MESA and

TESE, consist of medically extracting sperm from the epididymis or testicles. In 1996, Dutch IVF

professionals decided to withdraw MESA and TESE from clinical application because of the lack

of safety evidence and effectiveness in humans. The Minister of Health asked the Health Council

to advice on the matter. The Council concluded that animal research was needed to provide

sufficient evidence of safety. Because ‘regular’ ICSI was already successfully applied to humans

that much, it remained allowed in clinical practice, but under strict conditions (Gezondheidsraad,

1996).

At the time, there was no adequate animal model to investigate the safety of ICSI, but the

technique was introduced into clinical practice anyhow. This means that with the introduction of

ICSI, hardly any adequate safety research was performed and if any precaution was taken, it “was

to prepare a specific informed consent to make patients aware of the lack of data supporting the

safety of this micromanipulation technique” (Harper et al., 2012, p. 305). This means that the

clinicians were aware of the lack of safety evidence at that time. Considering the fact that there

was so little safety proof at that moment, it would have been better if “more basic research and

follow-up studies in the embryo, such as monitoring development and analysis of aneuploidy,

metabolism and methylation and paediatric follow-ups…” were performed (Harper et al., 2012,

p. 305).

25

2.1.3. Mitochondrial Supplementation / Augment treatment

If anyone might think that trial-and-error safety research is only a matter of the past, he or she

could not be more mistaken. In December 2014, the US company OvaScience announced that

they would introduce their new treatment, ‘Augment’, commercially. This mitochondrial

supplementation treatment would enable older women to supplement the energy of their egg cells

and improve pregnancy chances when previous IVF treatment is failing.

The Augment treatment consists of extracting mitochondria (which generate the energy of

a cell) from the ovarian stem cells of a woman and injecting them during IVF into her own egg

cells. This means that before fertilization, the woman has to undergo an ovarian biopsy. Here,

pieces of the ovary’s outer layer are extracted. In this tissue reside ovarian stem cells that are

harvested, counted and frozen. When the egg cell is retrieved, the mitochondria of the ovarian

cells are isolated from the thawed stem cells. Thereafter they are prepared and injected in the egg

cell during IVF together with the sperm (Motluk, 2015). The treatment uses techniques that are

similar to IVF and ICSI, although the insertion of the woman´s own mitochondria into her egg

cell is a relatively new element to the ‘traditional’ treatments. The technique is a variant of an

older technique that used donor mitochondria. The older technique was however not continued,

because of the lack of safety research. (Fakih et al., 2015).

Regarding the success and safety of Augment, Michael Fakih, owner of one of the few

centers that offers Augment treatment, and his team, argue in an article on the treatment that “the

support and use of the Augment treatment is based upon case reports of clinical success using

human donor egg cytoplasm injection as well as multiple published animal studies that have

demonstrated that the addition of mitochondria during IVF treatment is safe, improves the quality

of the embryos, and increases the success of IVF”. This seems however a very weak claim,

because the research they refer to considers a similar, but different technique to perform the same

treatment as the ‘new’ technique. This technique was first practiced in the 1990s and was

introduced into clinical practice without safety research. It consisted of using the cytoplasm

(where the mitochondria are located) of young, healthy, donor eggs and injecting that into

patient’s egg cells to improve the quality of the egg and embryo. Although 50 babies were born,

the treatment was not continued because more research on the safety of the technique was

required (Fakih et al., 2015). The safety and success of Augment is thus based on the cytoplasm

26

treatment of the 90’s, which is first; a different technique than Augment uses, and second; has

been argued for that it needed more study.

Apparently, Augment builds its safety evidence on the fact that 50 babies without

significant deviations were born after the old treatment. However, the lack of safety research

remains a fact. The old treatment that the developers of Augment refer to has been proven to not

guarantee sufficient evidence of safety. This means that the old treatment cannot be used to serve

as safety evidence for the new treatment. First of all, the research performed on humans

concerned ooplasmic transplantation (J. Cohen et al., 1998), which differs from the technique

used in Augment. In a case of ooplasmic transfer, ooplasm from the eggs of a donor are injected

into the eggs of the patient. The injected egg is then fertilized with sperm and implanted into the

womb of the patient. This is different from the process the contemporary Augment treatment

entails. It is therefore insufficient to use this example to argue for the safety of the Augment

treatment. Furthermore, the same study concerns treatment with egg cell donors, whereby the

Augment treatment concerns tissue from the patient herself.

Then, in the case of animal studies, the reference Fakih uses only refers to unpublished

animal studies. Apparently, although Augment treatment was introduced commercially in 2015

(Fakih et al., 2015), it was not until a year later, in 2016, that animal research in pigs suggested

that the treatment might actually be successful and safe (Cagnone et al., 2016).

Last, what is maybe most surprising, is the fact that the research Fakih refers to concludes

with: “In our opinion, the presented technology is highly experimental and it would be wise to

delay its widespread medical application until further studies in animal models and donated

human material indicate the best approaches” (J. Cohen et al., 1998, p. 279). The reason for its

delay is the fact that the treatment raised safety concerns to use donor’s mitochondria (Motluk,

2015). Although current Augment treatment uses the patient’s own tissue, this does not mean that

all safety dangers regarding the mother and the potential child are automatically avoided.

Therefore, Augment is forbidden in the United States (Motluk, 2015).

It seems that OvaScience introduced Augment treatment into clinical practice without

sufficient evidence on safety or effectiveness. While IVF as well as ICSI had proven their

effectiveness, when OvaScience announced that they were introducing the treatment: “No clinical

data on efficacy were provided, though they noted that 150 women had been enrolled in

27

experimental trials at four sites worldwide. These include the Toronto Centre for Advanced

Reproductive Technology (TCART) and clinics in London, Istanbul and Dubai” (Motluk, 2015).

The question then remains; why did OvaScience introduce the technology without

sufficient safety research? When OvaScience voluntarily suspended their US trial with the Food

and Drug Administration (FDA) in September 2013, they claimed that they were not aware that

Augment treatment needed regulatory approval. They argued that since the treatment consists of

injecting a woman’s own tissue into her own egg using ICSI, the method is similar to using ICSI

with only sperm. Instead of meeting terms with the US regulations, the company decided to move

their headquarters to the UK (Motluk, 2015). Augment is currently practiced in a few selected

clinics in Canada, Panama, Spain, Turkey, the United Arab Emirates, and Japan (OvaScience,

2016).

In relation to the example of IVF, the regulations in this case might also be perceived as

‘too’ strict by OvaScience, which can explain the company’s choice to avoid the regulation issue

by moving to another country. Anyhow, it resulted in the fact that there was no to little preclinical

testing before introducing it into clinical trial. Also, in relation to ICSI, the developers of

Augment knew (after the FDA trial) that there was no sufficient safety evidence. Just like in the

case of ICSI, researchers ignored the request of the FDA to improve research procedures. Instead

of improving their research, they continued their business by moving the treatment to other

countries.

2.2. Recommendations

As discussed, several ARTs have been introduced without sufficient preclinical safety research.

But as also follow-up studies or clinical practice have been scarce, it is still unclear to what extent

fertility treatments may have long term health consequences for mother and child. For the

mother, because of the risks of the medical procedure and for the child, because of potential

procedure-related abnormalities. According to Michèle Hansen and her team, it is widely

acknowledged that “infants conceived following in vitro fertilization (IVF) and intracytoplasmic

sperm injection (ICSI) are more likely to be born preterm, of low birth weight and to be a twin or

higher order multiple than spontaneously conceived infants” (Hansen, Bower, Milne, de Klerk, &

Kurinczuk, 2005, p. 328). In their research to find evidence supporting this claim, Hansen et al.

found out that indeed infants that are born following ART treatment have an increased risk of

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birth defects, in comparison to ‘naturally’ conceived infants (Hansen et al., 2005, p. 336).

Although it is unclear if these abnormalities are a result of the medical procedure or of the

subfertility of the parents, it remains a fact that the technologies need more study to investigate

the (origin of the) risks. The fact that until now no serious health problems related to fertility

treatments have come to light, should not be taken as a ground for complacency. Clearly,

introducing new ARTs into clinical practice without adequate safety research, including

preclinical studies and long term follow-up, would be irresponsible towards the primary

stakeholders: the women exposed to the relevant technologies and the children born as a result.

This section will build further on the argument that safety research in ART should be

improved (Dondorp & de Wert, 2011; Harper et al., 2012; Pennings et al., 2007). In medicine

there are two forms of innovation; formal research and innovative treatment. Formal research

refers to a systematic research process, mostly consisting of preclinical research, clinical trial and

follow-up research. Innovative treatment is “what clinicians do when they try something new that

has not yet been thoroughly tested in a research setting”(Dondorp & de Wert, 2011, p. 1). This

section examines European and American recommendations on both forms of innovation to

improve this research.

2.2.1. ESHRE

In 2007, the Task Force on Ethics and Law of the European Society of Human Reproduction and

Embryology (ESHRE) published a statement on the welfare of the child in medically assisted

reproduction. ESHRE points out that “the widespread adoption of new techniques frequently

takes place without the necessary evaluation of their efficacy, effectiveness, safety and social and

economic consequences” (p. 2587). This leads to possible risks inherent in the technologies and

medical treatments themselves. Therefore, sufficient safety research should be performed to

provide the welfare of the child (e.g. preventing malformations), public health (e.g. preventing

multiple pregnancies) and to inform potential parents to enable them to make better informed

decisions (p. 2587).

To ensure sufficient safety research, four steps are recommended; a) animal studies, b)

preclinical embryo research, c) clinical trials and d) follow-up studies. As this thesis concerns

embryo research, I will focus on the second step. Preclinical embryo research should be

considered where there is reason to believe that such research would enable to study “the

29

influence of different factors and interventions on the development and growth of the embryo,

epigenetic processes, genetic health, etc.” (Pennings et al., 2007, p. 2587). If this is the case, then

such research is crucial to arrive at a better understanding of the consequences of altering the

fertilization process of the embryo, thus reducing the uncertainty inevitably involved in the step

from animal research to human experiments. Withholding preclinical embryo research would

then mean that women and children are exposed to potentially greater risks than necessary

(Pennings et al., 2007, p. 2587). In the light of the need to take account both of the interests of the

would-be parents and of the welfare of the future child, this would be morally problematic.

2.2.2. ACOG

The American College of Obstetricians and Gynecologists (ACOG) supports the necessity for

safety research on embryos by using another argumentation than ESHRE (ACOG, 2006b).

Instead of arguing that such research is necessary because of the welfare of the future child, they

argue for its necessity in view of the patients’ right to be properly informed about the benefits and

risks of medical treatment as part of ‘informed consent’. According to them, “in some cases […]

innovative practice that appears to be safe and effective may become accepted practice, even if it

has never been subjected to formal research and an evidence base has never been developed to

support efficacy and safety. When this happens, patients and practitioners are left without the

data they need to make adequately informed decisions”(ACOG, 2006a, p. 1590). According to

ACOG, research should be performed to make sure that patients and clinicians can be well

informed about the treatment they are going to engage with. Without sufficient data on the safety

of the treatment, it is not possible to fully provide informed consent. This means that except for

the reason to provide a safe treatment to patients, there is also the argument that safety research is

necessary to provide informed consent. Without a sufficient evidence base, it is impossible for

them to make an informed decision.

Although the introduction of innovative practices and techniques is necessary for medical

progress, they should be subjected to systematic formal research in the following conditions;

(1)“in the absence of formal research”, (2)“without an adequate evidence base” and (3)“without

adequate data on the risks and benefits of new treatments” (ACOG, 2006a, p. 1594). The first

case addresses the necessity to have data for assessing the risks and benefits. When innovative

practices and techniques are introduced without systematic formal research, the data to assess the

30

risks and benefits are lacking. In the second case, practioners do not have the knowledge to

decide if an innovative technique is safe and effective enough to treat their patients. This means

that without adequate data practioners cannot make a responsible decision towards their patients.

In the last case, patients are unable to make an informed decision without the adequate data. This

makes it impossible to provide informed consent (ACOG, 2006a, p. 1594).

For a practioner to decide if innovative practice should be subjected to formal research,

one of three criteria should be satisfied. First, when the innovation is significantly different from

standard practice. Second, when the innovation has risks that are not known or that do not weigh

up against the potential benefits. Last, when the innovation is likely to result in generalizable

knowledge and depend on results of formal clinical trials (ACOG, 2006a, p. 1594).

2.2.3. ASRM

The American Society for Reproductive Medicine (ASRM), builds further on the

recommendation to perform safety research on embryos. Instead of making recommendations on

the necessity of such safety research themselves, they argue that such research should be proven

necessary by the investigator. According to them: “In view of the level of interest in embryo and

gamete research, this Committee advises that the investigator bears the burden of demonstrating

that the proposed studies merit using human gametes or embryos, that there is no adequate

alternative research methodology, that the study is likely to yield important scientific or clinical

data, that the number of gametes or embryos will be the minimum required for adequate study

design, and that risks to donors will be minimized”(ASRM, 2014, p. 333). Furthermore, there

always must be an approval from an ethics committee for the research project and informed

consent from every prospective participant before any research is performed on his or her

donated cells, embryos or tissues (p. 333).

2.3. Recommendations in practice

Although there are several good recommendations on how to safely introduce new ARTs

(ACOG, 2006a, 2006b; ASRM, 2014; Pennings et al., 2007), these are often not followed in

practice. As seen in the cases of IVF, ICSI and recently Augment treatment, recommendations

were ignored and the necessary research was not performed. Harper points out that “as time is

money, many of these new techniques have not been shown to be safe, to have a clear clinical

31

benefit and/or not been properly validated. This is a very worrying situation that may become

even more common as new technologies are developed” (Harper et al., 2012, p. 303).

Some might argue, that it takes a long time to perform the necessary research and

withhold medical development. Systematic formal research can be very time consuming. As seen,

time was for Jason Biggers the reason to reject the recommendation to perform research on

monkeys (Summers & Racowsky, 2008). Spending more time on research can be very expensive

and also means not receiving money from patients during this period. This might also explain

why ICSI was introduced despite the failing animal models. Also in the case of Augment,

OvaScience seemed to introduce the treatment as soon as possible. When the trial would almost

hold the company back, it just decided to move and offer their treatment in the countries where

regulation did not hold them back. Derived from the fact that OvaScience voluntarily suspended

their trial and only provides their treatment in a few selected countries, companies like

OvaScience might try to avoid the regulations and move to counties with softer regulations to

continue their treatment. The message on their website that their treatment is not offered in all

countries due to difference in regulation only supports this (OvaScience, 2016).

Time consuming safety research does not only bring negative financial effects to

introducing a technology, but also has to face the pressure of patients. Implementation of

innovations is often patient-driven. There can be pressure of patients to introduce the treatment as

soon as possible. Especially after positive media attention (Dondorp & de Wert, 2011, p. 4).

In the example of IVF, Edwards’ and Steptoe’s application was declined by the MRC

because the proposed preclinical research could not be ethically justified according to the council.

Because the council did not recognize the importance of treating infertility, they set the bar for

safety very high. The council wanted Edwards and Steptoe to perform primate studies first and

considered their proposed research too ‘experimental’, since it would subject woman to a still

experimental technique (laparoscopy) (Johnson et al., 2010). When their application was denied,

Edwards and Steptoe had to rely on private funding, which led to improper safety research. Also

in the case of embryo research, it appears that ethical issues withhold proposed research. While

embryo research is pleaded for by many authors (Brison et al., 2013; Dondorp & de Wert, 2011;

Pennings et al., 2007), it cannot always be sufficiently performed. While the use of spare

embryos is accepted by a lot of countries, these embryos cannot always be used, because for

some ART research, specially created embryos are needed. In the case of SCD Gametes for

32

example, embryos need to be created with these artificial gametes to investigate the safety and

effectiveness of the technology. This is problematic, because creating embryos for research is in a

lot of countries in Europe prohibited. Therefore, it is impossible to perform embryo research on

ARTs with specially created embryos in these countries.

However, Harper argues, “with so many examples where data now show that the

techniques that have been applied to thousands of patients have no clinical significance […], we

have to be fair to the patients” (Harper et al., 2012, p. 309). Without the evidence of the

effectivity of a technique, it is irresponsible to subject patients to the safety risks of new

treatments. The recommendations from ESHRE, ACOG and ASRM explicitly underline the

importance of responsibility towards the patients and future children (ACOG, 2006a, 2006b;

ASRM, 2014; Pennings et al., 2007). Although the introduction of IVF and ICSI were very

significant in reproductive medicine, both were introduced into clinical practice without any

safety evidence. As seen with Augment treatment, effectiveness as well as safety were not proven

before OvaScience introduced it in several clinics.

In conclusion, while many researchers emphasize the fact that there is a lack of sufficient

preclinical research on the safety and effectiveness in ARTs (Brison et al., 2013; Dondorp & de

Wert, 2011; Harper et al., 2012; Pennings et al., 2007), the current practice of introducing new

technologies generally does not respond to this observation3. Although this can have various

reasons, responsibly introducing a new technology does need sufficient research on the safety and

effectiveness before exposing it to patients. As seen in the introduction of Augment treatment,

new technologies are, despite all the recommendations, still introduced into clinical practice

without sufficient evidence of safety and effectiveness. This means that introducing new ARTs in

clinical practice with the current way of safety research procedures would be irresponsible

towards would-be parents and potential children. Therefore, safety research procedures should be

improved and applied in practice. This concerns also the safety research for the responsible

introduction for SCD gametes in specific.

3 One exception is the introduction of Mitochondrial Replacement Therapy (MRT) in the UK. MRT is subjected to a

systematic process of preclinical research and regulation. One important element of regulation considers the

restriction to only transferring male embryos. Because the long-term effects of MRT are not known yet, currently

transferring only male embryos avoids germ-line issues, since mitochondria are normally inherited exclusively from

the mother (National Academies of Sciences Engineering and Medicine, 2016).

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The creation of SCD Gametes is an emerging development in the field of ART. Although the

development is still at a research stage, current research suggests medically assisted reproduction

using SCD-gametes is a possible scenario (particularly for couples currently dependent on donor

gametes for reproduction) in the near to midterm future (Hendriks et al., 2015; Hinxton, 2008;

Marques-Mari et al., 2009). In an environment where ARTs are often introduced without

sufficient safety research, the possible introduction of SCD gametes in medically assisted

reproduction raises the question how this introduction should be safely performed. Therefore,

embryo research as a possible element of safety research on SCD Gametes will be investigated.

In this chapter I will first discuss the envisaged reproductive application of SCD gametes.

Thereafter, I will give an overview of the current state of research. Last, I will investigate the

utility of preclinical safety studies using embryos, for which embryos will have to be created

from donated gametes.

3.1. Envisaged applications of SCD gametes

As a new ART, SCD gametes can have many applications. One can think of SCD Gametes as a

fertility treatment for those presently dependent on reproduction using donor gametes.

Furthermore, in addition to reproductive goals, SCD gametes can be useful in research. It has

been argued that SCD gametes can help in fundamental research to understand the development

of sperm- and egg cells and of early embryos (Hinxton, 2008; ZonMw, 2012).

The introduction of SCD Gametes in medically assisted reproduction would make it

possible to treat multiple patient groups facing problems with reproduction. People who were

born with a condition that would render them infertile or who became infertile during their lives

could be helped with this technique. When ‘traditional’ IVF and ICSI treatments cannot offer a

solution to their problems, the use of SCD gametes to produce embryos with those techniques

34

possibly can. Now, people with such infertility problems are dependent on donor conception.

Medically assisted reproduction using SCD gametes would make donor conception redundant. In

contrast to conception with the use of donor gametes, the conceived child would be genetically

related to both parents (ZonMw, 2012, p. 31). To give an example, from e.g. skin cells taken

from an infertile man pluripotent stem cells could be created, which could in turn be

differentiated into sperm cells and thereafter used to fertilize an egg cell of his partner. This way,

the child would have half of the genetic material of both parents.

An example of another patient group are women and children needing fertility threatening

medical interventions. They are now dependent on gamete vitrification and egg- and sperm

maturation technologies (Loren et al., 2013). When the medical interventions would cause

fertility problems, they could use their preserved gametes. With the introduction of SCD gametes,

patient-specific gametes can be created after they are cured (ZonMw, 2012, pp. 31-32). This

would mean that gamete preservation would not be necessary anymore, because when the

medical intervention would cause fertility problems, SCD gametes could always be created.

Post-menopausal women would also be a potential patient group for SCD gametes.

Sometimes women get into menopause at a really young age. This way, they could still have

genetically related children. Of course, the age up to where post-menopausal women should be

helped to get pregnant is still considered highly debatable (Leridon, 2004; Mertes & Pennings,

2010).

Additionally, if some serious issues could be overcome, it could also give same-sex

couples a method to create children of which they are both a biological parent (Mertes &

Pennings, 2010; Testa & Harris, 2004, 2005). This would mean that, for example, in a case of an

all-male couple, SCD egg cells can be created from a pluripotent cell from one of the men. An

SCD egg cell will thereafter be used to fertilize the naturally obtained sperm cell from the other

man (ZonMw, 2012). This way, with the help of a surrogate mother, all-male couples can receive

their own biologically related child. However, this is more complicated than with heterosexual

couples, because the derivation of oocytes (XX) from an XY stem line, or even more problematic

sperm cells (XY) from an XX stem line, is more likely to have chromosomal problems than

derivation of a sex cell from the same sex (Hinxton, 2008; Mathews et al., 2009; Testa & Harris,

2005).

35

Also, the use of SCD gametes can improve IVF treatment, because the technique requires

in vitro growth and maturation procedures that will make hormone stimulation redundant. In IVF,

hormone stimulation is used to make women produce more than one egg cell per cycle, which

makes it possible to retrieve more egg cells for treatment. Women who are now dependent on

hormone stimulation to undergo IVF treatment, can use SCD gametes to create the necessary

amount of grown egg cells.

Another application of SCD gametes would be the ability to make the donation of egg

cells for research and therapy redundant. The demand for donor egg cells could put women under

pressure to donate (Beeson & Lippman, 2006). The use of SCD gametes could make the

argument that the creation of embryos for the purpose of research or therapy would put too much

pressure on women less relevant, because the demand of donor egg cells would be decreased

(ZonMw, 2012). As for research purposes, researchers would not be dependent on donation of

egg cells anymore to perform research with specially created embryos. In stem cell research, the

amount of egg cells needed to develop only a small amount of stem cell lines is extremely large

(Newson & Smajdor, 2005). If it is possible to create egg cells out of pluripotent stem cells, these

‘artificial egg cells’ can be used for research purposes (ZonMw, 2012, pp. 29-30). This

possibility to obtain a large amount of egg cells, could boost stem cell research and its envisioned

applications like treatment of Parkinson’s disease or cancers enormously (Newson & Smajdor,

2005).

In addition to research purposes, SCD gametes can thus also be used in therapy for the

treatment of e.g. Parkinson’s disease or cancers. In each case where non autologous (not derived

from the patient’s own stem line) embryonic Stem Cells (ESC) are needed, the use of donor

gametes for the necessary Somatic Cell Nuclear Transfer (SCNT) procedure would be needed. If

these donor gametes could be replaced by SCD gametes, the need for donor gametes (in specific

egg cells, which are difficult to obtain in contrary to sperm) would decrease even more. On the

long run, SCD Gametes could make the use of donor gametes redundant. However, until SCD

gametes are sufficiently tested on efficiency and safety, donor gametes (e.g. egg cells) will be

needed for research on SCD gametes.

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3.2. Current state of research

Multiple strategies to create gametes in vitro are explored (e.g. K. Hayashi et al., 2012; K.

Hayashi et al., 2011; Katsuhiko Hayashi & Saitou, 2013). These procedures are described in a

systematic review by Hendriks et al in 2015 (Hendriks et al., 2015). Hendriks et al describe eight

biologically plausible strategies to create human SCD gametes in males, and nine plausible

strategies in females. Furthermore, they describe nine biologically plausible strategies to create

SCD oocytes in males and nine plausible strategies which could result in SCD sperm in females

(Hendriks et al., 2015). The procedures are divided into three different kind of pathways

following the type of cells that are used; germline stem cells (GSCs), embryonic stem cells

(ESCs) and induced pluripotent stem cells (iPSCs). GSCs are stem cells that are produced in the

ovaries or testicles and can only differentiate into gametes. These cells are multipotent and not

pluripotent. I will not discuss this pathway, because this thesis envisions a broader application

beyond the maturation of GSCs. When using GSCs, only subfertile people with problems

considering the maturation of their gametes could be treated. Therefore, in this thesis, the focus

will be on gametes derived from PSCs, of which the use can potentially help people to have

children who do not even have anything in terms of early germ cells to start a growth and

maturation process with. Currently, there are two promising pathways for deriving SCD gametes

with PSCs; to use Embryonic Stem Cells (ESCs) or to use induced pluripotent stem cells (iPSCs).

3.2.1. Embryonic Stem Cells

After four to five days after fertilization, embryos reach the blastocyst stage. A blastocyst is an

early-stage preimplantation embryo. Embryonic Stem Cells (ESCs) can be derived from the inner

cell mass of the blastocyst. These cells are pluripotent, which means that they can develop into

any type of body cell, and may thus yield tissue for different kinds of regenerative medicine

(think e.g. of deriving dopamine producing cells to treat patients suffering from Parkinson’s

disease, or heart muscle cells for patients with cardiomyopathy), potentially also including the

derivation of gametes for medically assisted reproduction.

A necessary method to create patient-specific ESCs is the use of Somatic Cell Nuclear

Transfer (SCNT). The ESCs need to be patient-specific if you want to prevent rejection after

transplantation procedures. Moreover, in SCD gamete procedures, the patient-specific ESCs are

needed to make sure that the potential child is genetically related to the parents. In SCNT an

37

embryo is generated by replacing the nucleus from the egg cell by the nucleus of a somatic cell.

This procedure is often called ‘therapeutic cloning’ (Lanza, Cibelli, & West, 1999; X. Yang et al.,

2007). Although SCNT has not yet been successfully conducted in humans and is still in a

fundamental research phase (Dondorp & de Wert, 2007), it could theoretically be used for

patient-specific therapeutic applications like treating Parkinson’s disease or cancer (Barberi et al.,

2003; Byrne et al., 2007; Lanza et al., 1999). In such a case, genetically identical ESCs derived

from the created embryo would be used for cell replacement therapy. Because the embryo from

which the cells are derived has the same genetic material as the patient, this results in patient

specific PSCs, which are very unlikely to be rejected. The same technique can also be used for

reproductive purposes. In that case, it results in patient-specific PSCs from which gametes will be

created that are genetically identical to the patient.

Human SCD Sperm from males and SCD eggs from females have been only successfully

derived from non-patient-specific ESCs (Hendriks et al., 2015). Despite close attempts

(Tachibana et al., 2013; Yamada et al., 2014), creating human patient-specific ESCs using SCNT

still has not been achieved without significant drawbacks (e.g. considering the development of

the embryo). However, although not yet successful in humans, fertilization and live-birth

offspring has been achieved in animals using recipient-specific ESCs (Hendriks et al., 2015). One

of the leading research groups using SCNT succeeded to produce SCD gametes from mouse

ESCs in 2012 (K. Hayashi et al., 2012). They did so by acquiring naïve mouse ESCs from an

intermediate epiblast-like state after SCNT. Additionally, ESCs resulted in deriving eggs from

male mouse cells and were fertilized with SCD sperm from the same male mouse (Kerkis et al.,

2007).

A potential issue with this procedure (SCNT) is that the cells may retain a somatic

epigenetic memory (R. K. Ng & Gurdon, 2005). Such memory could lead to biases or limitations

concerning the differentiation into cells of a particular lineage. Gene expression and therefore the

properties and behavior of the cell may be altered. As a result, the altered gene expression would

be passed on to the future child, which could lead to imprinting disorders or subtler health-related

consequences not manifesting until after adulthood (Grace & Sinclair, 2009). For example,

research in mice has shown that human overgrowth syndromes, such as the Beckwith-

Wiedemann syndrome (BWS), are associated with errors in an imprinted cluster of genes on

human chromosome 11 (Sinclair, Young, Wilmut, & McEvoy, 2000).

38

Furthermore, SCNT has two additional ethical concerns. First, isolating the inner cell

mass of the blastocyst to create ESCs means the destruction of the embryo, which is ethically

sensitive. Second, to perform SCNT donor egg cells are needed, at least in the research phase.

After that, non-patient specific SCD egg cells might be used for therapeutic applications,

including for the creation of patient specific SCD gametes for reproduction through SCNT. The

need for donor egg cells could pressure women to donate egg cells, which concerns collaborating

in the riskiest element of IVF procedures; the hyper stimulation and extraction of egg cells. Both

issues will be addressed in chapter four of this thesis.

3.2.2. Induced Pluripotent Stem Cells

The second procedure, iPSCs will directly lead to patient-specific gametes without the in-

between step of creating an embryo through SCNT. The procedure concerns the reprogramming

of differentiated somatic cells (any kind of body cell) to induce pluripotentiality (S. Yang et al.,

2012). This is performed by introducing a set ‘reprogramming factors’ to the body cell. The four

factors, discovered by Shinya Yamanaka, are forced over-expressions of pluripotency genes and

reprogram the somatic cell into an iPSC (Takahashi & Yamanaka, 2006).

In animals, artificial sperm and artificial oocytes generated from iPSCs have been created

(Hendriks et al., 2015). Furthermore, research has succeeded to create fertile mouse offspring

from oocytes derived from skin cells using this procedure (K. Hayashi et al., 2012).

Just like the procedure using ESCs following SCNT, there is the possibility that iPSCs

retain a somatic epigenetic memory, which could lead to health-related consequences for the

future child. The procedure using iPSC has the advantage over SCNT in that there is no need to

create an embryo as an in-between step. This makes the procedure less technically difficult than

SCNT and also less ethically sensitive. In the case of ESCs, there is the moral issue of creating

embryos that will not be used for pregnancy each time SCD gametes would be created. This

means that next to possibly creating embryos in the context of safety research, also the treatment

itself would involve the creation and destruction of embryos. In addition, using iPSCs also

excludes the possible pressure on egg cell donors for the reproductive procedure, since no donor

egg cells would be needed.

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3.3. Utility of preclinical safety studies using human embryos

Although it is still difficult to predict the time frame when clinical application of SCD gametes

would be possible, Hendriks et al. expect the introduction to be possible in the intermediate

future. However, the safety and functionality of SCD gametes in humans is still to be proven,

since the first human SCD gametes still have to be produced (Hendriks et al., 2015).

It is argued that the procedure with SCD gametes, like several ARTs, can disrupt the

process of genetic imprinting (Grace & Sinclair, 2009; R. K. Ng & Gurdon, 2005; Sinclair et al.,

2000). Because the safety concerns, the UK allows the use of SCD gametes for safety research,

but banned their use for human reproduction (HFEA, 2009). There first needs to be more data on

the possible health risks before the treatment can be introduced into the clinic (ZonMw, 2012).

3.3.1. Systematic Formal Research

Research has recommended a process of animal research, preclinical embryo research, clinical

trial and follow-up studies to investigate the safety and effectiveness of ARTs, and specifically of

SCD gametes (Brison et al., 2013; Dondorp & de Wert, 2007, 2011; Hinxton, 2008; Pennings et

al., 2007). As described in the previous chapter, the history of ARTs shows that such research

was and still is often neglected. However, these steps are crucial to determine the safety of SCD

gametes. Animal research can give insight in potential transgenerational effects by performing

follow-up research on multiple generations (Brison et al., 2013; Dondorp & de Wert, 2011).

Non-human primates would be ideal for this research, because of their close resemblance to

human beings. However, such research is very expensive, time-consuming and ethically sensitive

(ZonMw, 2012, p. 37). To narrow the gap between animal research and clinical research,

preclinical embryo research can be performed (Dondorp & de Wert, 2011; Hinxton, 2008). After

positive results, the treatment can move to clinical trial. If it has been proven to be sufficiently

safe and effective, the technology can be introduced in the form of clinical studies determining

efficiency and investigating the conditions under which the procedure can best be offered.

Follow-up research helps to keep track of the effects of the treatment (including long-term safety)

and may lead to its adaptation.

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3.3.2. Preclinical Embryo Research

Since the aim of this thesis is to investigate the ethical justifiability of embryo research on SCD

gametes, I will focus on this part of the safety research procedure. As already briefly explained in

the previous chapter, preclinical embryo research forms an important step in safety research on

ART. To follow the internationally recommended ‘chain’ from experimental procedures to

follow-up research (ACOG, 2006b; Pennings et al., 2007), safety research on SCD gametes

ideally should include preclinical embryo research. In this section, I will explain the necessity of

embryo research in safety research more extensively.

In 2013, professor of clinical embryology and stem cell biology Daniel Brison, published

an article on how to assess the safety of IVF technologies. According to him, a very important

part of preclinical testing should be embryo research: “much of our knowledge of the impact of

assisted reproduction treatment on the embryo comes from assessments of embryo developmental

progression in culture and embryo morphology” (Brison et al., 2013, p. 714).

Brison is not the first to recommend embryo research on new ARTs (Dondorp & de Wert,

2011; Hinxton, 2008; Pennings et al., 2007), but he makes its benefits to safety research very

explicit. He explains that it is very important to examine the gene expression patterns of

preimplantation embryos. In the gene expression of the embryo, maternal as well as paternal

genes are reorganized. The process by which an embryo begins to transcribe its newly formed

genome is called embryonic gene activation. Following Brison, “embryonic genome activation is

essential to the development of the embryo and can thus be used as a global marker of embryonic

health” (Brison et al., 2013, p. 715). Furthermore, gene expression of embryos is affected by

epigenetic regulation (Chason, Csokmay, Segars, DeCherney, & Armant, 2011), that can result in

‘environmental cues’ (Brison et al., 2013, p. 715).

According to Brison, as a result after gene expression research, embryo development

highly differs between one embryo and the other. While large numbers of embryos are used in

animal models like mice, performing large embryo studies are constrained by several issues, like

scarcity and ethical difficulties. This results in embryo research with embryos from couples with

problems concerning fertility. Therefore, it cannot be assumed that the development of embryos

in the laboratory represents ‘normal’ embryo development (p. 715). Therefore, Brison et al. argue

that it is “essential to study the impact of new technologies on embryo development using

embryos donated to research as fresh embryos, cryopreserved embryos, fresh or cryopreserved

41

oocytes which can be activated to generate embryos for research and human ESC lines generated

from equivalent embryos” (Brison et al., 2013, p. 717).

3.3.3. The creation of embryos for research

Like with all new ARTs, the safety of SCD Gametes should be investigated before introducing it

into clinical practice. Since preclinical embryo research is essential in safety research on new

ARTs (Brison et al., 2013; Dondorp & de Wert, 2007, 2011; Pennings et al., 2007), it can be

argued that preclinical safety research should also be included in the safety research on SCD

Gametes. Recent research has shown the effectiveness of using specifically created embryos to

preclinically investigate the safety and effectiveness of mitochondrial replacement therapy

(Hyslop et al., 2016) and the Hinxton Group explicitly recommends preclinical embryo research

on SCD Gametes as this would narrow the gap between animal research and first clinical studies

(Hinxton, 2008).

In some cases of research on ARTs, spare embryos after IVF can be used for preclinical

embryo research. However, research on the safety of SCD gametes needs to be performed with

specially created research embryos. After all, the research concerns primarily the process before

fertilization. Therefore, to test the safety of SCD Gametes, the embryos need to be created by

using these gametes. The use of spare embryos after IVF would thus be ineffective, since they are

generated with ‘normal’ gametes.

This chapter examined the possible advantages of introducing SCD Gametes, its

technical pathways and limitations, and the necessity to perform preclinical embryo research to

responsibly introduce the technology into clinical practice. The next chapter explores the

arguments of those rejecting either all forms of (instrumentalizing) embryo research as well as of

those only rejecting research for which embryos would need to be created. Furthermore, the

arguments of those supporting embryo research in general as well as the arguments of those

supporting the use of specifically created embryos for research will be investigated.

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43

Many researchers have argued that using embryos for safety research can be of significant

importance (Brison et al., 2013; Dondorp & de Wert, 2011; Pennings et al., 2007), it nevertheless

leads to several ethical issues. The use of specifically created embryos for research is regarded as

problematic by several commentators. Arguments against the creation of embryos for research

refer to the status or value of embryos and/or to the risk that women will be pressured into

donating oocytes against their best interest or exploited (Baylis, 2000; Dickenson, 2002;

FitzPatrick, 2003; Gerrand, 1993; Hoedemaekers, 2003; Murphy, 2012; van Beers, 2009). Some

of those opposing the instrumental use of embryos see no difference between the use of spare

embryos or embryos that are specially made for the purpose, rejecting all research not intended to

benefit the embryo in question (Hoedemaekers, 2003). However, others accept the use of spare

embryos for research, but find the intentional creation of embryos as research material

unacceptable (FitzPatrick, 2003; Murphy, 2012; van Beers, 2009). This distinction is reflected in

the fact that many countries with legislation regulating embryo research reject the creation of

embryos for research, but allow the use of spare embryos under conditions of proportionality and

subsidiarity. In this chapter, I will describe the ethical debate, identified in the selected literature,

concerning the use of embryos for research and the creation of research embryos. I argue that this

debate can be structured around three main ethical issues.

First, general moral arguments considering the acceptability of embryo research will be

mapped. The debate will be illustrated by three views on the moral status of the human embryo. It

will be shown that the perspective on the moral status of the embryo is determining the

perspective on the acceptability of embryo research. The second section concerns the ethical

debate on the creation of embryos for research. If embryo research can be justified in general, can

then also the creation of embryos for research be justified? Building further on the second

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section, the last section will describe the ethical debate on how to responsibly obtain the required

oocytes. If embryo research, and the creation of embryos for research, can be justified, how

should we deal with obtaining donor oocytes? It will be argued that the necessity of obtaining

donor oocytes can also be used as a moral difference between using leftover embryos for IVF and

creating embryos for research.

4.1. Ethical perspectives on embryo research

Is embryo research acceptable? To investigate this essential basic question, the safety benefits of

embryo research are balanced against the moral harm of destroying early stage human embryos.

It is also possible to perform research on embryos benefiting the embryo and without destroying

it. This is known as therapeutic embryo research. This thesis will focus solely on embryo research

that involves destroying the embryo, as this would also be the case in embryo research on SCD

gametes. The benefits of embryo research are already explained in chapter two and three (21-42).

We have seen that embryo research would improve safety research on ARTs, so that they could

be responsibly introduced into clinical practice. Also briefly discussed in chapter two and three is

the drawback of embryo research concerning the destruction of the embryo, which is necessary to

perform the research.

Can the destruction of embryos be balanced against the benefits of preclinical embryo

research? To measure if the benefits outweigh the harms, it is key to define the moral status of the

embryo. An entity has a moral status if it has moral interests that matter for that entity’s own sake

and which can be wronged (Jaworska, 2013). If a being has a moral status, we are obliged to

consider its needs, interests, or well-being when we are making decisions towards it (Warren,

1997). Some philosophers have argued that moral status comes in degree, of which full moral

status is the highest (DeGrazia, 2008; Sumner, 1981). Their hypothesis that “the moral status of a

being is proportional to its degree of sentience helps to explain why it is reasonable to distinguish

between the moral status of (for instance) fleas, sparrows and human beings” (Warren, 1997, p.

87). It is important to define the moral status of the embryo, because it determines the moral

weight of using and destroying it. To give an example, if an embryo would have the same status

as a human being, destroying the embryo would mean the same as to kill or perhaps murder a

human being. Would it have no moral status at all, there would be no harm in using it for

research. Therefore, the ethical justifiability of embryo research is centered on the moral status of

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the embryo. The relation between moral status and justification of embryo research will get more

clear in the next paragraphs.

The Health Council of the Netherlands published a report in 1998 summarizing the three

main views considering the moral status of the embryo (Gezondheidsraad, 1998, p. 60).

4.1.1. The moral status of the embryo is the same as the moral status of a born human individual

According to the first view, the moral status of the embryo is the same as the moral status of a

human being. Therefore, embryos should be protected to the same level as born human

individuals should be protected (Gezondheidsraad, 1998, pp. 60-61).

This view can be identified in the work of e.g. philosopher Stephen Buckle, who has

argued according the respect for the capacities of individuals argument that “respect is due to an

existing being because it possesses the capacity or power to develop into a being which is worthy

of respect in its own right; and respect is due to such a being because it is the very same being as

the later being into which it develops. The already-existing being is a being which has the

potential to become a being worthy of respect in its own right” (Buckle, 1988, p. 230). Because

the zygote can be identified with the later person, Buckle argues that it is entitled to the same

respect as the later person. This however does not apply to separate egg cells or sperm cells,

because they are not an ‘individual’ yet. They cannot be identified with the later person and

therefore do not have to potential to develop into that specific individual (Buckle, 1988).

The view that embryos deserve the same respect as human beings, or something close to

it, can also be seen in the regulation on embryo research in Germany, as well as in the view on

embryos of the Catholic Church and orthodox Protestants. The German Law forbids nearly (e.g.

abortion is allowed) all actions with embryos that may harm the embryo. Also oocyte and embryo

donation are forbidden (ZonMw, 2012, p. 77). To harm the embryo for a purpose other than its

own means to fully instrumentalize it. Instrumentalization of the embryos means that the embryo

is not seen as an end in itself, but only as an object for us to use to reach a specific goal. Key of

the argument behind the German Law is that such instrumental use of an embryo is not

commensurable with their high moral status. Therefore, the German Law forbids every

instrumental use of an embryo (ZonMw, 2012, p. 81).

Furthermore, in the 1988 report of the scientific bureau of the Dutch democratic Christian

party (CDA), it has been argued that embryos leftover after IVF may not be destroyed nor used

46

for research (CDA, 1988). According to the report, human life deserves protection regardless the

stage of development. This means that born as well as unborn individuals deserve the same level

of protection. To destroy a spare embryo after IVF would mean to instrumentalize human life,

because life is destroyed when it is no longer perceived as useful anymore (CDA, 1988, p. 93).

This applies as well to using spare embryos for research, since this would also mean to

instrumentalize the embryo and to deny its high moral status (CDA, 1988, p. 93). Supporters of

this view consider the embryo to have the potential to grow into a human being and to interrupt

this process cannot be justified.

In my view, the argument by proponents of this view consists out of two parts. The first

part considers the argument that early stage embryos are the same individuals than the later

persons they (potentially) grow into. Because of the potential the embryo has to develop into the

later person, embryo and born human individual should be protected equally. To interrupt the

process of development of the embryo is thus perceived impermissible. The second part of the

argument considers the instrumentalization of human life. According to this argument, it is

impermissible to use human life for a purpose other than its own. Since the use of embryos for

research means to destroy them, the embryo is used without any interest for its own. Because the

embryo is considered equal to the later person it can develop into, instrumentally using embryos

is equally impermissible than instrumentally using (and destroying) grown human individuals.

4.1.2. Embryos have symbolic worth at best

Another view is that embryos do not have a moral status on which ground they should be

protected. This view is more theoretical than that it can be found in practice. According to this

view, embryos should not be treated any differently than the gametes from which they derive.

However, not having an intrinsic moral status does not mean that embryos should not be

protected at all. For instance, the symbolic worth of an embryo can be used as an argument to

protect it. The symbolic worth refers to the social connection the embryo has with all humans

(Gezondheidsraad, 1998, p. 61). The embryo is in this case not protected because of its intrinsic

moral value, but because of the community ascribing it meaning as a starting form of human life

(Sandel, 2004). This means that such a given meaning can differ between cultures and time

periods. Contrary to the division of the Dutch Health Council, the position of symbolic worth can

be better classified as a category of the next view where embryos also have a limited worth of

47

protection. Therefore, from now on, I will use the view on symbolic worth of the embryo as a

category of the next position.

4.1.3. Embryos have a limited worth of protection

A third view holds the middle between high and no protection and considers embryos to have a

limited worth of protection. This view does not consider the embryo a human being, but still

thinks that it can be granted moral value because the embryo can potentially grow into a human

being. In contrary to the first view, that used potentiality to argue for no difference in moral

status, authors supporting this view have argued that the potential to grow into a human being

that embryos have, grants them a degree of, but not full, moral status (Harman, 1999, 2003) or

enhance their moral status (Steinbock, 2011). This means that the embryo does have a moral

status, but this status is not equal to the moral status of a born human individual. Often, it is

added that the embryos have an increasing worth of protection. This means that the worth of

protection increases the more the embryo develops (Gezondheidsraad, 1998, pp. 61-62).

Also the previously discussed symbolic worth of the embryo can grant the embryo limited

worth of protection. Only in that case, the worth of protection is not granted because of its

intrinsic value, but because of the fact that it has a social connection with the human species,

since the meaning of the embryo is ascribed by the community.

The view that embryos deserve limited protection can be seen in e.g. the Dutch embryo

law (CBO, 2003). According to this law, it is permissible to use embryos for research only when

specific criteria are met. For example, in article 10, it is written that embryo research is only

acceptable when it is very likely that the research will lead to new insights in medical science.

Furthermore, the research using embryos is only permissible when it cannot be performed using

other methods of scientific research (CBO, 2003). The fact that these criteria need to be met in

order to justify the use of embryos for research, means that it is unacceptable to use embryos for

every arbitrary purpose. This means that embryos deserve protection according to this view. Yet,

if these criteria are met, the use of embryos for research is acceptable, which means that embryos

do not deserve full protection. The Dutch embryo law thus proclaims the view that embryos have

a limited worth of protection.

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4.2. Ethical perspectives on creating embryos for research

In some cases of embryo research on ARTs, using spare embryos is insufficient; to obtain a result

it is necessary to specially create embryos for research (e.g. on SCD gametes). In this thesis, I

will only focus on the arguments considering the acceptability of the use of research embryos in a

case where spare embryos are insufficient for research. This leaves the waste principle (using

spare embryos because it is better to use them than to do nothing with them) out of account. Also

the subsidiarity principle, stating that embryos should not be created for research when spare

embryos can be used, is thus not relevant.

Following the previous section, proponents of two out of the three views (potentially)

accept the creation, use and destruction of embryos for research. The first view, which considers

embryos to have the same moral status as human persons, clearly is against all deliberate harm

and destruction of embryos. Proponents of this position leave no room for the use of embryos for

research, regardless of whether the embryos are surplus after IVF and donated for research (spare

embryos) or created solely for research purposes. Therefore, there is no need in examining this

view any further in this chapter.

The second view considers embryos to not have any moral status on which ground they

should be protected. This view does not make a difference in moral status between spare embryos

and research embryos as well, since both types of embryos should not be treated any differently

than any other body tissue. Because this position is generally non-existent in practice and does

not oppose embryo research more than any other research containing human body tissue, there is

no need for a further examination of this view in this chapter either.

The middle view however (including symbolic worth of embryos), does leave room for

discussion on the moral acceptability of creating and destroying embryos for research purposes.

Since proponents of this view consider embryos to have a limited worth of protection, some

purposes (e.g. research concerning the treatment and prevention of serous human diseases and

suffering) using embryos could be justified (Brock, 2010). If embryo research can be considered

acceptable following this view, can it also be justified to create embryos for the purpose of

research?

Currently, in most countries in Europe, the creation of embryos for research is not

allowed. The use of spare embryos for specific research (serving an important purpose) is in most

countries authorized. Apparently, a moral difference is made using spare embryos (accepted) and

49

creating embryos for research (forbidden). If there would be no moral difference between using

spare embryos that already exist and intentionally creating embryos for research, it could be

argued that the use of research embryos should be allowed just like the use of spare embryos is,

or that the use of both type of embryos should be forbidden. The moral distinction between spare

embryos and research embryos has been a debate in the field of embryo research identified in the

selected literature, in which one position suggests that there is indeed a moral distinction between

spare embryos and research embryos that would require prohibiting the creation of research

embryos (FitzPatrick, 2003; Murphy, 2012; van Beers, 2009), while others argue that there is no

moral difference between using spare embryos and research embryos (Brock, 2010; Devolder,

2005, 2013). This section will focus on the ethical arguments opposing and supporting the

creation of embryos for research.

4.2.1. Inherent moral status

Is it possible that the authors arguing for a difference in moral acceptability between using spare

embryos and creating embryos for research mean that there is a difference between inherent

moral statuses of both types of embryos?

Following the middle position (that considers embryos to have an increasing worth of

protection) an embryo does not have the same moral status as a full human person, but it

nevertheless has a certain moral status on which ground it should be protected. This status is, as

described above, related to the potential or symbolic worth of the embryo. According to this

view, embryos morally deserve a certain respect, because they are a human species or can

potentially develop into a person (Brock, 2010; Gezondheidsraad, 1998).

Supporters of the potentiality argument of the middle position grant a moral status to the

embryo based on internal characteristics, because they consider the embryo more valuable than

other human tissue (Devolder, 2005). These internal characteristics can be described as biological

properties allowing the embryo to grow into a human being. The embryo is thus considered a

biological entity, yet also a potential human being. Following the view of limited value based on

potentiality there cannot be found a moral difference in status between spare embryos and

research embryos. Both types of embryos have the intrinsic biological properties to grow into a

human being. Whether the embryo actually becomes a person is considered not relevant to the

protection we have to give it. In both cases they have the capacity to become humans, and in both

50

cases they are destroyed when they are used for research. Thus, there is no moral difference

between spare and research embryos based on their intrinsic potential (Gezondheidsraad, 1998).

Also in the middle position based on a symbolic, social value of the embryo, there cannot

be found a difference considering inherent moral value between spare embryos and research

embryos. Both spare embryos and research embryos have the biological properties that make

them socially seen part of the human species.

Furthermore, the fact that the middle position acknowledges increasing protection of the

embryo the more it develops, emphasizes the focus on the internal biological characteristics of

the embryo. Following the element of increasing worth of protection, there can be found no

difference between both types of embryos, since both embryos are used for research at the same

stage of development. Thus, one type of embryo is not further developed than the other, leaving

both kinds of embryos with the same level of protection worthiness.

The literature does not mention a moral difference between spare embryos and research

embryos based on a difference in moral status of the embryo as entity. I have not found any

author arguing for such difference in moral status. If the authors did not argue for a difference

between the intrinsic moral value of spare embryos and embryos created for research, what could

then be their argument for allowing research with spare embryos but not allowing creating

embryos for research?

4.2.2. Intention

Clearly, the authors who point out a difference between using spare embryos and specially

created embryos for research do not aim at a difference in moral status considering internal

factors. An alternative option that has been argued for is that a moral difference can be made

between the intention of creating spare embryos and creating research embryos (FitzPatrick,

2003; Murphy, 2012; van Beers, 2009).

Britta van Beers, professor in the department of Theory of Law and Legal History at the

University of Amsterdam, has pointed out a difference in intention of creating IVF embryos and

research embryos (van Beers, 2016). She argued that the creation of embryos for the purpose of

research introduces a new category of human life that is only intended for instrumental use

instead of serving a ‘relational value’, such as reproductive purposes (van Beers, 2016). Van

Beers argues that research embryos are intentionally created as a subcategory of human life that

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will never grow into human beings, which in her view is at odds with the protection that embryos

deserve. In the case of spare embryos, the embryos were at least created with a relational value in

mind, namely helping a couple with reproduction.

Biomedical philosopher Timothy Murphy has argued for a moral difference in intention

as well (Murphy, 2012). Murphy supports his statement by arguing that the principle of double

effect can justify embryo deaths in natural reproduction and IVF, but not for research. Following

the principle of double effect, it can be justified to bring about harm when it is a foreseen but

unintended side effect of an action that is aimed at some good end (McIntyre, 2004). An action

thus has two effects; one that is intended and one that is a side effect, or “double effect”. The

principle of double effect stresses that “if the evil effect is brought about as a means to the good

effect, then the evil effect must be intended, and the bringing about of the instrumental state of

affairs is morally impermissible” (Boyle, 1980, p. 531). This means that bringing about harm can

only be justified when it is not the means for an end, but a side effect that accompanies getting to

that end. The principle of double effect will be further explained in chapter five. For now, this

brief explanation will be sufficient.

According to Murphy, embryo loss in fertility medicine using IVF is not intended, but

only foreseen. This differs from the intentional destruction of embryos that occurs in research

(Murphy, 2012, p. 531). Embryos leftover from IVF were not created with the intention of

destruction, because their deaths are not the means for reproduction. In the case of research

embryos however, destruction of the embryos is intended, because the research performed on the

embryos necessarily involves the destruction of the embryo. Therefore, the intention of

destruction is already present when creating the embryo. The destruction of the embryo is the

means for research.

Murphy’s argument thus states that morality depends on intention. He gives the example

of natural reproduction, where many embryos fail to implant or lead to embryo-loss or

miscarriage; “conception in vivo does not require any intent to expose embryos to the risk of

death, the embryo loss that occurs is not the means by which successful conception occurs, and

the effect of having children is as important as any to be found in human life” (Murphy, 2012, p.

532). The moral difference lies in the ‘means’ as intention. While in IVF and natural reproduction

embryo deaths are not the means for new life, embryo deaths are necessarily the means to

perform embryo research.

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Also using double effect reasoning, moral philosopher William FitzPatrick has argued

that the moral difference between using spare embryos and creating embryos for research lies in

the intent/foresee distinction (FitzPatrick, 2003). According to FitzPatrick, IVF clinicians foresee

that probably not all embryos will result in a child. However, they do not create embryos with the

intention to destroy them. On the contrary, when creating embryos for research, we are “creating

embryos with such an intention, exhibiting the distinctively exploitative and opportunistic

attitude bound up with such a practice”(FitzPatrick, 2003, p. 31).

Emphasizing the intentional destruction in the creation of research embryos, FitzPatrick

argues that since the research necessarily involves the destruction of the embryo, performing the

research and destroying the embryo are in a constitutive relation. In other words, the relation

between the creation of embryos for research and their destruction is of excessive closeness

(FitzPatrick, 2003, p. 32). According to FitzPatrick, the possible destruction of embryos in IVF is

merely a causal relation, in which it is possible to aim at the one without aiming at the other. This

is different to the constitutive relation between creating embryos for research and destructing

them, because these two things are “too intimately connected to speak of aiming at the one

without aiming at the other” (FitzPatrick, 2003, p. 32). Because of this constitutive relation, to

create an embryo for research thus means to create an embryo for intentional destruction, which

cannot be justified.

Thus, using spare embryos for research is perceived to be more commensurable with the

value of the embryo than creating embryos for research. FitzPatrick argues that in creating

embryos for research, we are taking an intrinsically inappropriate attitude towards early human

life (FitzPatrick, 2003). Because of the constitutive relation between research and destroying the

embryo, research embryos are always created with the intention to destroy them (FitzPatrick,

2003). This is considered incommensurable with the limited moral value granted to embryos.

Others have described the inappropriate attitude as the ‘instrumentalization’ of embryos (van

Beers, 2009), whereby embryos are solely created and used as a means for our own interests

(Murphy, 2012).

Opposing the view that intention grants a moral difference between using spare embryos

and research embryos, bioethicist Katrien Devolder argues that if standard IVF practices are

allowed, it would be no different to allow the creation of embryos for research (Devolder, 2005,

2013). In most countries where IVF is practiced, on average five to ten embryos are produced per

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IVF cycle. One or two of them are transferred to the woman’s womb in a single cycle to try to

achieve a pregnancy. Even if several subsequent transfer cycles are tried, many embryos still end

up in the freezers of fertility centers and will eventually be destroyed. The reason why more

embryos are created than can be responsibly transferred in one cycle is to enhance the

effectiveness of IVF. This is in the interest of women undergoing IVF, as the alternative would

require more stimulation cycles and thus expose them to higher burdens and risks. For this

reason, the present approach in which more embryos are created than will be needed may be

called ‘woman-friendly IVF’ (Devolder, 2013). The majority of embryos created for woman-

friendly IVF will thus not be used by the couple. As a result, these embryos will remain frozen,

will be donated to other couples or for research purposes or will be destroyed. In practice, spare

embryos are rarely used for reproduction purposes for other couples, which means that the

majority of embryos will never result in a child. An alternative method would be to only create

one or two embryos per cycle (which is the maximum that can be responsibly transferred to the

womb in order to avoid the risks connected to multiple pregnancies). This may be called

‘embryo-friendly IVF’ (Devolder, 2013). Until its recent revision, this was required under the

Italian embryos act: in order to protect embryos from destruction, it was not allowed in Italy to

create more than three embryos per cycle, each of which had to be transferred to the womb (Setti

et al., 2010). However, this increases health risks and discomfort for the woman and decreases

her chances of having a child through IVF. Therefore, standard IVF practice in most countries

involves woman-friendly IVF.

Devolder argues that since the gross majority of the early stage embryos in our standard

way of performing IVF (woman-friendly IVF) will not be used for implantations into the womb

of a woman, just like research embryos will not, there is no moral difference in creating spare

embryos or research embryos. According to Devolder, “couples or individuals who create spare

embryos apparently believe that the enhanced chance of a successful pregnancy and of fulfilling

their wish for a child outweighs the moral value of each of the embryos” (Devolder, 2005, p.

181). The opponents of creating embryos for research, who base their argument on a distinction

on intention, seem to consider early embryos as a group, arguing that as it is not known which

embryo will eventually be chosen for transfer to the womb, it can still be said that the whole

group of embryos is created with the intention of letting those embryos grown into a child

(Devolder, 2005, p. 182). However, when considering each embryo separately, it is known

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beforehand that the majority of embryos created for woman-friendly IVF will remain unused.

Therefore, the embryos are created with the knowledge that most of them will never result in a

child, just like embryos created for research are not. According to Devolder, to argue that each

and every embryo created with woman-friendly IVF is created with the intention to let it grow

into a child would thus be inconsistent, while so much would be needed to argue a difference

between an intention to create embryos as ends in themselves (in IVF) versus creating them fully

instrumentally as mere material (in research).

Furthermore, is has to be questioned whether in IVF the benefit of reducing harm to the

woman due to potentially more hormone treatments and further egg retrievals is large enough to

outweigh the morally challenging embryo deaths of spare embryos (Devolder, 2013, p. 535).

According to Devolder, the principle of proportionality cannot be met in standard IVF and

embryo research when the embryo is considered to be a person. Otherwise, it would mean that

one thinks that the intentional creation and destruction of persons to reduce harm for another

person or for research purposes would be acceptable. If one does think double effect can justify

standard IVF, the moral status one accords to the embryo must be low. If it is that low, “how can

it provide a decisive reason against sacrificing embryos for research that can potentially save and

improve the quality of life of a very large number of people”? (Devolder, 2013, p. 536).

Another argument for allowing the creation of embryos for research states that neither the

creation of an embryo, not its use and destruction, is bad or impermissible. Therefore, the

combination of the three elements should not be morally problematic either (Brock, 2010).

Medical ethicist Dan Brock argues that an embryo lacks sentience or consciousness, and

therefore does not have interests or a good of its own. Therefore, it does not have any specific

interest in remaining alive (Brock, 2010). “If they [embryos] cannot have an interest in becoming

a person because they do not have any interest at all, then they cannot have a right to become a

person and realize their potential” (Brock, 2010, p. 236). Following this line of argument, using

and destroying already existing embryos does not harm them. Given the benefits of e.g. stem cell

research, the use and destruction of embryos can be justified. Also the creation for the purpose of

research is not intrinsically immoral, argues Brock. According to him, “no one believes that the

creation of an embryo is in itself morally wrong and impermissible, and most do not believe that

doing so by artificial means such as IVF is either” (Brock, 2010, p. 237). In the eyes of Brock,

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combining the creation and the use and destruction of embryos should be just as justifiable as

both elements separately.

Devolder and Brock thus both argue in favor of creating embryos for research. Devolder

states that creating embryos for research is not any less ethically justifiable than creating spare

embryos in standard IVF practices. If we allow standard IVF practices, we should also allow the

creation of embryos for research (Devolder, 2005). Since spare embryos are created as an

external means to a parental project, just like research embryos are created as an external means

to the ends of scientific research, the element of intention does not draw a moral line between

them. Also the principle of proportionality is used to argue in favor of creating embryos for

research. If it would be proportional to sacrifice spare embryos for the benefit of women, it would

also be proportional to sacrifice research embryos for the benefit of knowledge. Brock’s

reasoning follows a different path. Instead of focusing on the intention and proportionality of the

creation embryos for research, he tears apart the element of creating embryos and using and

destroying embryos for research. Since both elements separately are not intrinsically morally bad,

the combination of them should not be morally bad either (Brock, 2010).

4.3. Ethical perspectives on obtaining donor egg cells

Another problem that rises with the creation of embryos for safety research is the demand for

donor egg cells. Instead of arguing for a difference in intention in using spare embryos and

creating embryos for research, this pathway problematizes the creation of embryos for research

out of concern for the interests of women. To create embryos for research, egg cells and sperm

cells are needed. Sperm cells are relatively easy to obtain, since these cells can be taken after

normal ejaculation. Egg cells however, are much more difficult to obtain. Therefore, how to

responsibly obtain egg cells forms a great part in the ethical debate on creating embryos for

research.

4.3.1. Risks and benefits

In egg cell donation, women have to undergo several risks. First, these women have to take

hormone medication to induce their ovulation and to increase their egg cell production. These

medications have been associated with risks like ovarian hyper stimulation (Griesinger, Diedrich,

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Tarlatzis, & Kolibianakis, 2006). Second, the egg retrieval procedure can lead to physical pain

and injury. Last, the practice can bring about psychological and emotional stress (Baylis, 2000).

In IVF practice, the benefit for the woman undergoing these procedures is clear. The risks

are accepted, because the treatment can help to pursue the reproductive goal of the woman. In

donating for another woman the motive may be altruism: the wish to help an infertile couple to

fulfill their child whish. In donating for research however, women undergo hormone stimulation

therapy and invasive medical procedures, when there is no concrete benefit for the woman

(Gerrand, 1993). The woman does not experience any direct or indirect health benefit. Also, in

most cases, the women cannot choose the recipients benefiting from their egg cells for research

or therapy. Last, it is very likely that the women will not benefit financially from collaborating in

research (Baylis, 2000). If there are no benefits for women donating their egg cells, what then

would be the motivation to participate?

4.3.2. Coercion and exploitation

The creation of embryos for the purpose of research can increase the risk of coercion for women

(Baylis, 2000). The demand for donor egg cells can put vulnerable women under pressure. To

give an example, the Korean researcher Hwang Woo-suk was accused of fraud in 2006. He

claimed he succeeded to create embryos by cloning. It appeared that the data were fabricated and

the research was misconducted (SNU, 2006). Although the research was not a success, he

nevertheless needed many egg cells. It turned out that he gained the egg cells by pressuring his

female employees from his laboratory (ZonMw, 2012, p. 30).

It has been argued that the creation of embryos might threaten women’s autonomy

(Gerrand, 1993). One aspect of being an autonomous agent is to be able to give informed consent

to any procedure. Also choice and voluntary actions are aspects which play a role being an

autonomous agent. Because the risks and long-term effects of hormone-stimulation are not fully

understood yet, it is impossible for women to make a fully informed choice about egg donation

(Gerrand, 1993). However, it has been argued that the risks of using hormone-stimulation

medicines are negligible when responsibly using the medicines (Devroey, Polyzos, & Blockeel,

2011). Nevertheless, even if fully informed consent was possible, this does not mean that the

risks of exploitation of women in vulnerable circumstances vanishes. For instance, the

exploitation of women in a low financial environment would be still conceivable.

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Moreover, several authors argued that ARTs cause several social concerns, including the

possibility that women would be perceived as just being reproductive vessels (Arditti et al., 1984;

Corea, 1985; Rowland, 1992). It is argued that if such a perception would result from using

ARTs, this perception could certainly arise when women are used for harvesting eggs in order to

create embryos for research, leading to the exploitation of women (Dickenson, 2002; Gerrand,

1993).

Altogether, the creation of embryos for research does not only bring ethical concerns for

the embryos, but also for women. In egg cell donation, women are exposed to practical and social

problems; practical, because of the hormone therapy and invasive IVF procedure without

knowing the risks, and social, because of a potential exploitation of women by perceiving them as

just being reproductive vessels. Both practical and social problems threaten women’s autonomy

in making informed and voluntary choices (Gerrand, 1993). By threatening the autonomy of

women potentially participating in egg donation, without any physical, personal, or financial

benefits, the risk of coercion and exploitation of women should be properly addressed in the

discussion on research embryos (Baylis, 2000; Gerrand, 1993).

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For preclinically investigating the safety and effectiveness of SCD gametes in embryos, it is

inevitable that specific research embryos are created. In the previous chapter I have mapped the

ethical debate on the use and creation of embryos for research (pages 43-58). In this chapter, I

will assess this debate and investigate if and under which conditions the creation of embryos for

research can be justified in general, and specifically for research on SCD gametes.

The ethical assessment on the creation and use of embryos for research in this chapter will

be performed by using wide reflective equilibrium (WRE). The first part of this chapter will give

a brief introduction to procedural method of WRE. In the second part, I will assess the moral

acceptability of using (spare) embryos and creating embryos for research in general, using the

method of WRE. The third part will investigate the ethical justifiability of embryo research on

SCD gametes as a case study. One question to study is: if the use and creation of embryos for

research can be justified under specific circumstances, can it also be justified for research on

SCD Gametes? I will argue that the creation of embryos for research on SCD Gametes can be

justified, if the principles of subsidiarity and proportionality are met.

5.1. Wide reflective equilibrium (WRE)

In the first chapter of this thesis I argued why I chose for WRE to perform the ethical assessment

in this thesis (pages 17-19). In this section, I will explain how I will use this approach.

In Rawls’ theory there are three types of justification. The first is political justification,

which only takes into account political values. The second is full justification, which only focuses

on the own lives and comprehensive doctrines of citizens. In this thesis, I aim to reach the third

type; public justification. This is a justification by political society in which citizens take into

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account reasonable overlapping consensus (Rawls, 1993). The ground of justification is in this

case the shared political conception. In such overlapping consensus, “people with divergent

comprehensive doctrines can overlap in their acceptance of a conception of justice. They do not

have to agree on everything but they do agree on principles of fairness” (Doorn, 2011, p. 68).

This way, I aim to reach a ground of justification concerning the ethical justifiability of creating

embryos for research in this ethically diverging debate.

Building further on the work of John Rawls (Rawls, 1971), philosopher Norman Daniels

has given a structured description of the method of WRE (Daniels, 1979, 2011). According to

Daniels, “The method of wide reflective equilibrium is an attempt to produce coherence in an

ordered triplet of sets of beliefs held by a particular person” (Daniels, 1979, p. 258). In this

method, a distinction is made between the following three levels of considerations:

(a) a set of considered moral judgments

(b) a set of moral principles, and

(c) a set of relevant descriptive and normative background theories.

To use the procedure of WRE, one starts with collecting initial moral judgements. These are

considered ‘intuitions’ someone has about particular situations or cases (Daniels, 2011). Then,

alternative sets of moral principles should be proposed that all “fit” with the moral judgements to

various degrees. It is important not to choose the best fit right away, as this would provide only a

‘narrow’ equilibrium. One needs to use philosophical arguments to bring out the strengths and

weaknesses of the alternative sets of principles. These arguments can come from relevant

background theories. This means that the background theories should support the moral

principles that are chosen over alternative principles, independent from the match of moral

principles with one’s moral judgements (Daniels, 1979). It is important to aim at coherence

between the different levels (a, b and c) of considerations. This coherence can be reached by

going back and forth between the different levels of considerations and revising the

considerations, principles and theories that do not fit. This way, we arrive at a wide reflective

equilibrium. It is called an ‘equilibrium’ if all levels of considerations cohere and are mutually

supportive. We call it ‘reflective’ if the equilibrium is reached by going back and forth by

between the different considerations. The reflective equilibrium is called ‘wide’ if coherence is

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reached between all three levels of considerations and not only between one level (Doorn, 2011,

p. 66).

In the next section, I will use WRE as a method to assess the consistency between moral

judgments, sets of moral principles and background theories of different views on the

justifiability of the use and specifically creation of embryos for research purposes.

5.2. Acceptability of the use and creation of embryos for research

Before turning to the case study of SCD Gametes, I will assess the arguments for and against the

use of spare embryos and the creation of embryos for research in general using WRE. Based on

my analysis, I will draw my own conclusion regarding the moral acceptability of using embryos

for research.

In chapter four (pages 44-47) I have identified three different views considering the

acceptability of using embryos for research. From these three views, three different sets of moral

judgements and moral principles can be extracted. I begin this section with stating all considered

moral judgements and towards the use of embryos for research, the moral principles that fit these

considered moral judgements and all relevant background theories. I will show that each set of

principles is related to the theories of personhood and potentiality.

After the paragraphs on the justifiability of using embryos for research, I will assess the

acceptability of creating embryos for research, using the same method of WRE. I will compare

the moral intuitions, principles and theories on the creation of embryos for research to the

creation of spare embryos for women-friendly IVF.

5.2.1. A matter of moral status: personhood & potentiality

I have argued that three different positions regarding the acceptability of embryo research can be

distinguished. I explained that supporters of the first position argue that embryos have the same

moral status as born human individuals. Therefore, both should be protected to the same degree

(Buckle, 1988; CDA, 1988). To use embryos solely for research purposes means to

instrumentalize them, which cannot be justified considering their high moral status (CDA, 1988).

The considered moral judgement resulting from these considerations is that embryo research

cannot be justified. Furthermore, several moral principles can be identified in this view. First,

embryos and born human individuals have an equal moral status. Second, embryos and born

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human individuals should be protected because of their moral status. Last, to use embryos for

research instrumentalizes them, which is not commensurable with their high moral status.

Following the second position, embryos have no moral status on account of which they

should be protected. The considered moral judgement that can be identified here is that embryo

research is just as acceptable as research with other body tissues. In this view, the moral

principles consider moral status as well as in the first view. First, embryos have no moral status.

Second, body tissue has no moral status and third, because embryos have no moral status they

can be used under the same conditions as applying to research with any other body tissue.

The third view, holding the middle position, states that embryos have a limited worth of

protection in comparison to born human individuals (Harman, 1999, 2003; Sandel, 2004;

Steinbock, 2011). Because embryos have the potential to grow into a human being, or have a

symbolic worth that connects them to humans, they do not have the same moral status as human

beings, but a lower degree of moral status than born human individuals. In this view, the

considered moral judgement thus states that embryos should be protected to a limited degree.

This leaves the acceptability of using of embryos for research open. The first moral principle that

is made here is that moral status comes in degrees. Furthermore, embryos have a lower moral

status than born human individuals. Because of their lower moral status, they also have a lower

worth of protection. Last, the principle is used that the potential that embryos have to grow into a

human being or its symbolic worth grants them a degree of moral status.

What all positions have in common is that they (1) base their view about the worth of

protection of the embryo on their view on the moral status of the embryo, (2) make a moral

comparison between embryos and another entity (e.g. born human individuals or body tissues)

and (3) imply that born human individuals have full worth of protection, whereas body tissues

have none. Because all views base their position on the comparison of embryos to other entities

(e.g. born human individuals with full moral status), it is essential to investigate why we give a

moral status to specific beings and because of what qualities we grant them (full) moral status.

Therefore, to perform an ethical assessment on the three sets of principles, I will give a brief

introduction on the theories on which moral status is grounded; personhood and potentiality.

Following the systematic approach of Daniels (Daniels, 1979), this leads to the following triplet

of sets of considerations:

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(a) Moral judgements of the three views: embryo research aimed to preclinically investigate

the safety and effectiveness of specific technologies and methods can(not) be justified.

(b) Sets of moral principles of the three views: All consider the moral status and protection

worth of embryos. The question all views answer is: “is the use of the embryo for research

commensurable with its moral status?”.

(c) Background theories: personhood and potentiality

The main reason we think grown human individuals deserve protection is because we consider

them to be ‘persons’, having full moral status (DeGrazia, 1993; Warren, 1997). However, the

view that being a person grants a being moral status and protection, the ‘person view’, does not

automatically solve the issue of moral status though (Reinders, 1993). The question remains what

the criteria are for being a person. What features make a being a person?

Several philosophers have answered the question on what criteria a being should meet to

qualify as a person by returning to philosopher John Locke (Baker, 2000; Harris, 1985; Singer,

1980; Tooley, 1983). Following Locke, a being is a person when it has a specific mental capacity.

A person should be able to imagine oneself in different times; past, present and future. This

means that a person needs to be conscious of itself. Thus, according to Locke, a being without

self-consciousness cannot be a person (Reinders, 1993). Although at several points departing

from Locke, philosopher Lynne Rudder Baker agrees with him that the distinction between a

person and a non-person lies in something mental. According to her, the possession of a first-

person perspective is the essential feature of personhood (Baker, 2000). A first-person

perspective must not be understood as a perspective from merely the biological body. According

to Baker, personhood is not defined by being an organism; a person is not essentially biological.

The essence of being a person is not to (only) have a body, but to have special mental properties

to provide a first-person perspective. Baker gives the example of wondering how one is going to

die or evaluating one’s desires (Baker, 2000). This resembles the interpretation of personhood of

philosopher Charles Taylor, calling persons self-interpreting animals (Taylor, 1985). Both

authors describe a reflection on one’s own life as an essential feature for personhood. However,

Taylor and Baker want to go beyond Locke, who defines persons as only self-consciousness in

the sense of distinguishing it from being a specific material or immaterial substance (Baker,

2000, p. 9; Moran, 2009). According to Taylor and Baker, being a person, a self-interpreting

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animal, is more than that. Our experience is, as Taylor calls it, necessary that of an embodied

agent (Taylor, 1995, p. 25). Baker emphasizes the necessity of embodiment as well: “a person is

[…] an embodied thinking substance with a first-person perspective (Baker, 2000, p. 77).

If a being is not capable of self-interpretation, does this mean that it has no moral status?

Several authors have argued that properties for personhood can come in degrees (DeGrazia, 1997,

2008; Sumner, 1981). Philosopher David DeGrazia has argued that personhood can also be

understood as a “cluster concept that serves as a summary placeholder for other concepts such as

moral agency, autonomy, the capacity for intentional action, rationality, self-awareness,

sociability, and linguistic ability” (DeGrazia, 1997). He argues that most of these properties can

come in degrees, meaning that moral status might not be just a case of all-or-nothing. Even

though a being is thus not considered a person with full moral status, it can have properties (e.g.

moral agency, autonomy, self-awareness) of a certain degree that we connect to personhood.

Having such properties to a certain degree can grant a being a proportional degree of moral

status. DeGrazia argues that many of these properties, besides language and autonomy, can be

found to a certain degree in many nonhuman animals (DeGrazia, 2008). Philosopher Leonard

Sumner argued for a degree of properties that grant moral status to beings as well. According to

him, the degree of moral status is connected with the degree of sentience (Sumner, 1981).

Examples of beings having a different degree of sentience are persons, sentient animals and late

fetuses. He argues that the degree of moral status is proportionate to the degree of sentience; “The

animal kingdom presents us with a hierarchy of sentience. Non-sentient beings have no moral

standing; among sentient beings the more developed have greater standing than the less

developed, the upper limit being occupied by the paradigm of a normal adult human being”

(Sumner, 1981, pp. 143-144).

Another ground for moral status, connected to the theory of personhood, is the potentiality

theory. I have explained in chapter four (pages 44-45) that proponents of the first view, stating

that embryos have the same moral status as born human individuals, grant full moral status to

embryos, because embryos are already considered as human individuals. Proponents of the

middle view argue that embryos can be viewed as beings actively developing their potential for

personhood. They argue that the potentiality to grow into human beings grant embryos a limited

moral status and proportionate worth of protection (Harman, 1999, 2003; Steinbock, 2011). In

both positions, the view that an embryo has the potential to develop in a human being grants it a

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degree of moral status. This means that the background theory of potentiality plays a role in

determining the moral status of embryos in both views.

Potentiality is a concept first introduced by Aristotle. Aristotle makes a distinction

between actuality and potentiality. Actuality is the current state of an entity. Potentiality is the

ability to be in a different and more completed state. In the case of a wooden table, actuality is to

potentiality as the wooden table to the wood. In the case of a human being, actuality is to

potentiality as a human to an embryo. In Aristotle’s teleological world view, potentiality is more

than just ‘possibility’ in the sense of ‘can become’. Rather, potentiality is what connects an entity

to its end or completion (‘telos’) by defining what it is intrinsically determined to become. In this

understanding, to say that an embryo has the potential to grow into a human being, is to say that it

is intrinsically determined to realize its completion as a human being. The potentiality of an

entity is its essence; an entity is essentially what it is meant to become (S. M. Cohen, 2016). This

is quite different from how potentiality is understood in a modern scientific world view, in which

the notion of an essence or an end generally cannot be understood as something apart from a

physical entity. In this understanding, potentiality refers to a contingent relation of mere

possibility: given the right circumstances, an embryo has the potential to become a human being.

I have shown that the theory of personhood supports the idea of moral status coming in

degrees. The highest degree of moral status, full moral status, is granted to beings which we can

consider persons. To call a being a person means that such a being has to have certain properties,

such as the ability to reflect on one’s life, embodiment and moral agency. If a being has these

properties to a certain degree, we grant it a proportionate degree of moral status.

In the debate about the acceptability of embryo research, the theory of potentiality is

highly connected to the theory of personhood, because the first and middle position contains

principles based on potential personhood. The first positon uses the theory of potentiality to argue

that embryos deserve the same respect as the human beings they can develop into. Supporters of

this position consider embryos as already being human individuals. The third position, the middle

view, uses the potentiality theory to argue for a limited worth of protection. Because an embryo

has the potential to grow into a human being, but is not already one, it deserves a degree of

respect. Having clarified the theories of personhood and potentiality, I will now continue

assessing the three positions on the use of embryos for research by testing their coherency with

these theories.

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5.2.2. The Justifiability of Embryo research

When going back and forth between the theories of personhood and potentiality and the moral

principles made in the first position, the views that embryos have the same moral status as born

human individuals, or persons, is only coherent with the background theory of personhood if

potentiality is understood as a teleological concept. Reasoning from an Aristotelian world view,

the essential continuity between the embryo and the human being that it will become (if no

external factors interfere with its completion) entails that embryos are to be considered as

essentially persons and that as such they have a full moral status and must be treated accordingly

(Eijk, 1997). Some proponents of this view specify that embryos deserve complete protection

only from the point (after about fourteen days) when they can no longer split in two, as only after

this stage it would be possible to ascribe a fixed individuality to each single embryo (Ford, 2002).

However, others do not regard this a relevant criterion and hold that human embryos deserve

complete protection already from the point of conception (Jochemsen, Garcia, Meir, & Harris,

2005; Vélez, 2004).

However, reasoning from a modern world view according to which potentiality refers to a

contingent possibility rather than to an essential continuity, there are many differences between

persons and early-stage embryos, which also grant a moral difference between them. As

described in the previous paragraph, persons should have the ability to interpret their own lives in

different times, which embryos in the early stages of development (fertilization stage, cleavage

stage, blastocyst stage) cannot. Also the other properties for personhood, such as moral agency,

autonomy and sentience or self-awareness cannot be identified in early-stage embryos. Therefore,

on a modern understanding of potentiality, it is not coherent to state that embryos have the same

moral status as born human individuals. This means that an early-stage embryo lacking these

essential properties does not deserve the same level of protection as a grown human individual

having these properties.

Moreover, saying that embryos are already persons essentially, is tantamount to saying

that they are not so actually. As argued above, the properties which are necessary for personhood

cannot be found in early-stage embryos. Insofar, the theory of personhood does not support the

idea that embryos would already be persons. Unless understood in an Aristotelian manner, the

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potentiality argument can thus not be used to argue that embryos are already persons, without

departing from the theory of personhood.

Furthermore, the position that embryos have the same moral status as persons is difficult

to combine with many accepted practices. Considering embryos as persons from the moment of

conception, does not leave any room for practices such as abortion, intra-uterine devices that

prohibit embryo implantation, and the creation of spare embryos in the context of IVF. These

practices assume that embryos and fetuses have a different moral status than born human

individuals. If we accept these practices, this cannot be coherent with the view that embryos have

full moral status.

The second position is coherent with the theory on personhood, as well as with the theory

of potentiality understood as referring to mere possibility. However, it does not accord moral

relevance to the fact that this possibility, however contingent, makes embryos different from any

ordinary human body tissue that cannot develop into a human being. Early-stage embryos have

the potential to develop the properties of personhood. By denying that this has moral relevance,

the second position is at odds with a widely held moral intuition.

The middle position, stating that embryos have a limited worth of protection, is also

coherent with the theories of personhood and potentiality. Embryos at the blastocyst stage do not

have the same properties as born human individuals, or persons, do. Since they cannot be

identified as persons, they do not have full moral status and should not be protected to the same

degree as persons. Using the potentiality argument, the potential of developing properties of

personhood can give the embryo a worth of protection, yet not to the same degree of beings

already possessing these properties. Also the argument of increasing worth (the more the embryo

develops and the more it develops the structures necessary for later having the properties required

for personhood, the more it should be protected) is in line with the theory that the properties of

personhood can come in degrees, and that beings having these properties to a certain degree

should be protected proportionate to the degree of owning these properties.

The second variant of the middle positon, using symbolic worth instead of potentiality,

states that the embryo should not be protected because of its intrinsic moral value, but because of

the community giving it meaning as a starting form of human life. Also this variant is coherent

with the theories of personhood and potentiality. The value given to the embryo is in this case not

because its being on its way to becoming a person would make it intrinsically valuable, but

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because its connection to the human species as an early form of human life gives it a symbolic

value. Still, it also acknowledges the potential the embryo has, because being a form of early

human life, means having the potential to grow into a more developed form of human life; a

person.

Altogether, both variants of the middle position are coherent with the theories of

personhood and potentiality, while also acknowledging the moral intuition that human embryos

have at least some (intrinsic of symbolic) value. Because early-stage embryos lack certain

essential properties of personhood to grant them the same high moral status as born human

individuals, they do not need to be protected to the same level as born human individuals. Yet,

the fact that the embryo can potentially grow into a human being and the symbolic worth of the

embryo grants it a limited degree of protection. Therefore, coherent with the theories of

personhood and potentiality and the widely shared intuition that embryos are morally more

special than just any body tissue, the moral value of an early-stage embryo is located between

high and no moral value, which means they deserve a limited degree of protection.

5.2.3. A matter of double effect and instrumental value

In the previous section I have argued that the middle view and its set of moral principles are

coherent with the background theories of personhood and potentiality, as well as with the widely

shared intuition that embryos have a least some (intrinsic or symbolic) value. This means that

within the framework of these theories, embryos have a limited worth of protection, which means

that the use of embryos for specific research (e.g. stem cell research) can potentially be justified.

Before I will move to the section investigating if the creation of embryos for the purpose of

research can be justified, I will first identify the moral judgements, moral sets of principles and

relevant background theories considering the creation of embryos for research.

I have argued in chapter four (pages 43-58) that the ethical difference between using spare

embryos and creating embryos for research is centered around two main arguments. The first

argument considers the intention of how these embryos are created. The second argument raises

concern on the possible exploitation of women to donate their egg cells. I will first focus on the

argument of intention.

Again, following WRE, I start with stating the considered moral judgements and

matching moral principles. These can be identified in the different views on the (non) moral

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difference between spare embryos and research embryos. A first view can be identified in van

Beers’ argument, which states that to create embryos with the intention to destroy them would

instrumentalize them (van Beers, 2016). She argues that research embryos are only created for

instrumental use, as against spare embryos that are created with a relational value; the

reproduction process. Therefore, it is acceptable to create spare embryos and not acceptable to

create embryos for research. The considered moral judgement in this view thus states that the

creation of embryos for research is not acceptable. The moral principle that is made here is that

the instrumentalization of embryos is wrong. She implies that an embryo that is created with a

relational value is thus not instrumentalized. The moral principle of this view is based on the

theory of instrumental value.

Murphy, as well as FitzPatrick, argue that the deaths of spare embryos in IVF are not

intended, but only foreseen, as against the intended creation and destruction of research embryos

(FitzPatrick, 2003; Murphy, 2012). In this view, the considered moral judgment is that the

creation of research embryos cannot be justified. The second set of moral principles can be

derived from their argument considering the acceptability of intentionally creating embryos for

destruction. One moral principle is; intentionally creating embryos for destruction is morally

wrong. A second moral principle states that it is permissible to create embryos that will be

destroyed when the destruction is not the means for the end, but only a side effect. What these

principles have in common is that they are both based on the theory of double effect.

A next alternative set of considerations can be identified in Devolder’s view. Devolder

argues against a moral difference between the intention of creating spare embryos and research

embryos. In both cases, the embryos are created to serve a purpose other than their own. In the

case of IVF, the creation of spare embryos reduces risks and enhances pregnancy chances for the

woman (Devolder, 2005). In the case of research, the creation of embryos helps to investigate the

effectiveness and safety of a technology or method. According to her, if we accept current IVF

practices (effective and therefore woman-friendly IVF) we should also accept the creation of

research embryos (Devolder, 2013). The considered moral judgment is thus that the creation of

embryos for research is acceptable. The moral principle that is made here states that because

embryos are justifiably instrumentalized in current IVF practices, instrumentalization of embryos

for research should also be accepted. She argues that double effect cannot justify the creation of

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spare embryos any more than research embryos. Here, the arguments are centered around the

theory of double effect and instrumentality.

The last set of considerations considers the argument of Brock. He argues that the creation

of embryos as well as the use and destruction of embryos is accepted, and that therefore the

combination of these practices should also be accepted. Here again, the moral judgment that can

be identified is that the creation of embryos for research is acceptable. The moral principle Brock

states is that if one action is considered justifiable and another action is considered justifiable, the

combination of them should also be considered justifiable. Since Brock implies that it does not

matter with what intention an embryo is created, used or destroyed, his argument should be able

to invalidate double effect reasoning. Therefore, also this set of principles is based on the theory

of double effect.

In all different views the moral principles consider the moral difference (or non-

difference) between the intention of creating spare embryos and research embryos. Furthermore,

the intention arguments against and for the creation of embryos for research are centered around

the theories of double effect and the instrumentalization of the embryo. This leads to the

following triplet of sets of beliefs:

(a) Moral judgments of all views: The creation of embryos for research is (not) acceptable.

(b) Sets of moral principles: Intention grants a moral difference between creating spare

embryos and research embryos versus there is no moral difference in intention between

creating spare embryos and research embryos.

(c) Background theories: double effect and instrumental value

Before assessing the coherence of all sets of principles with the relevant background theories of

double effect and instrumental value, I will first give an overview of these theories. The principle

of double effect has already been explained briefly in chapter four (page 51), where I explained

that the principle entails that causing harm can be justified when it is a foreseen but unintended

side-effect of an action aimed at a good end (McIntyre, 2004). It thus aims to justify an effect that

one normally finds impermissible, but that is a merely unforeseen side effect of a legitimate act.

The principle of double effect can be first located in Thomas Aquinas’ Summa Theologiae, in

which he (e.g.) treats homicidal self-defense (Aquinas, 1981). Nowadays, the principle refers to a

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set of ethical criteria, mostly but not exclusively used by Christian philosophers. To decide if an

act is morally permissible, the next four ethical criteria of double effect should be met; (1) the

nature-of-the-act condition, which states that the action itself should be good or at least

indifferent in itself, (2) the means-end condition; the good effect and not the harmful effect

should be intended, (3) the right-intention condition states that the harmful effect should not be a

means to the good effect and according to (4) the proportionality condition, the harm should be

proportionate to the good effect (Cavanaugh, 2007; Mangan, 1949).

The principle of double effect is used in several contexts, but often considers cases of

pregnancy and abortion (Bennett, 1966; Donagan, 1979; Foot, 1967; McIntyre, 2004). Imagine a

doctor who thinks that abortion is morally impermissible, even as a means to save the mother’s

life. However, the same doctor could believe it is permissible to perform a hysterectomy on a

pregnant woman with ovarian cancer (McIntyre, 2004). In performing the hysterectomy, the

doctor aims to save the life of the woman. He foresees the death of the fetus, but does not intend

to kill it. In performing an abortion, on the contrary, the killing of the fetus is a means to save the

mother. In this case the killing of the fetus is not foreseen, but intended. Thus, following the

principle of double effect, the killing of the embryo can only be justified in performing a

hysterectomy, in which the killing of the fetus is not intended, but only foreseen.

The concept that an entity can be ‘instrumentalized’ is based on the second background

theory; the theory of instrumental value. In philosophy, a distinction is made between intrinsic

and extrinsic, or instrumental, value. Intrinsic value is the value something has “in itself, or “for

its own sake” (Zimmerman, 2014). To give an example, a singer could say that she loves to sing.

If she loves to sing because of the singing itself, and not because she could get famous or earns

her money with it, singing has an intrinsic value to her. The opposite of intrinsic value is extrinsic

value. Extrinsic value is given to things not because they have value in itself, but because they

can lead to something else to which they are related in some way (Zimmerman, 2014). To use the

same example again, if the singer loved singing because she can pay her house and fancy car with

it, she grants an extrinsic value to singing. It has been argued that the relation between the end

and the extrinsic means to get to that end is an instrumental relation (Korsgaard, 1983). Going

back to the example, in the second case, the singer makes instrumental use of singing, to reach

her goal; a house and a fancy car. If we apply this on the creation of embryos, we could say that if

we use embryos to reach a goal, we are using the embryos instrumentally. If someone says that a

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specific action “instrumentalizes” embryos, he thus means that we use an embryo to reach a goal,

other than in the interest of the embryo. By using the embryo instrumentally, we give an

instrumental value to it.

5.2.4. The justifiability of creating embryos for research

Having clarified the theories of double effect and instrumental value, I will now assess the

coherence of the moral judgments, sets of moral principles and these theories. I will show that

double effect and instrumental value cannot provide a moral distinction between the creation of

embryos in standard IVF procedures and the creation of embryos for research.

The first set of moral principles I discuss is the set identified from the argument of van

Beers (van Beers, 2016). She argued that spare embryos in IVF have a relational value (a

parental plan), and research embryos only have an instrumental value. The moral principle that

can be identified states that it is morally wrong to instumentalize embryos. However, the

argument of van Beers is not coherent with the theory of instrumental value, because this theory

applies to research embryos as well as to spare embryos. In creating spare embryos for woman-

friendly IVF, the majority of embryos also serves as a means to reach a goal; to increase the

chances of a successful pregnancy and to decrease risk of the harms for the woman. This means

that in standard IVF practices, embryos are instrumentalized in order to perform a successful IVF

procedure.

Van Beers could reply that there is still a difference, because of the relational value of

spare embryos, since they are considered to be part of a parental plan. However, with this

response she would only confirm the fact that spare embryos are just as much instrumentalized as

research embryos. Following the theory of instrumental value, something has instrumental value

when it is (also) used to serve a purpose other than its own. To say that spare embryos have a

relational value because they are part of a parental plan, is to say that we use embryos

instrumentally to benefit this parental plan. Additionally, in the use of research embryos to

investigate the effectiveness and safety of ARTs, it can be argued that these embryos also have a

relational value. The goal of creating these embryos is to responsibly introduce ARTs into

clinical practice. These ARTs can be used to help several couples with their parental plans. The

argument of instrumental use and relational value can thus not be used to defend a moral

difference between spare embryos and research embryos.

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The following set of moral principles I discuss is the one from Murphy and FitzPatrick

(FitzPatrick, 2003; Murphy, 2012). According to this set of principles, intentionally creating

embryos for destruction is morally wrong. Furthermore, it is only permissible to create embryos

for destruction when the destruction is not a means to the end, but only a side effect. Murphy and

FitzPatrick argue that, using the principle of double effect, the destruction of embryos in standard

IVF is only foreseen, as against the intentional destruction of research embryos. However, does

double effect really justify standard IVF procedures? The creation of spare embryos in woman-

friendly IVF cannot be understood as merely foreseen, because one could very well limit the

creation of embryos to the amount (one or two) that can be responsibly transferred to the womb

in one IVF-cycle (embryo-friendly IVF). The majority however accepts current IVF practices and

sticks with woman-friendly IVF. This means that in a society that accepts woman-friendly IVF to

be the standard IVF practice, it is incoherent to say that creating embryos for research

instrumentalizes embryos and that creating more embryos than that will be used (spare embryos)

does not instrumentalize embryos. To make the choice to perform woman-friendly IVF,

necessarily means to intentionally create spare embryos that will be destroyed (or remain frozen)

and will thus not result in a child. Therefore, it is incoherent to argue that the creation of research

embryos not resulting in children is intended and the creation of spare embryos not resulting in

children is merely foreseen.

As to the intentional destruction of embryos, in performing woman-friendly IVF, the

procedure necessarily involves creating spare embryos. The gross majority of these spare

embryos will never be used for reproductive purposes (including by another couple). Even if (in

several subsequent cycles) all embryos created for woman-friendly IVF would be placed inside

the womb of the woman, it is indubitably known that the majority of embryos will not result in a

child and will thus die. Because standard woman-friendly IVF practices are intentionally chosen

over embryo-friendly IVF practices, double effect cannot justify embryo deaths in standard IVF

procedures and can therefore not be an argument for a moral difference between spare embryos

and research embryos.

FitzPatrick’s adds the argument of constitutive relation to the argument of double effect

discussed above (FitzPatrick, 2003). According to FitzPatrick, creating embryos for research is

morally different from creating embryos for IVF, because creating embryos for research and the

destruction of embryos is a constitutive relation. To create embryos for research, means thus to

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create embryos for destruction. However, it is incoherent to argue that the creation of spare

embryos is not intentionally in a constitutive relation with destroying them. Because choosing

woman-friendly over embryo-friendly IVF is so closely connected to creating spare embryos, it

cannot be argued that the creation of spare embryos is a merely foreseen and not intended

element of standard IVF. Therefore, using the argument on constitutive relation of FitzPatrick,

performing the standard IVF procedure and creating spare embryos are also in a constitutive

relation. Knowing that the majority of spare embryos will not be used for another couple’s

reproductive purposes, creating spare embryos automatically means that they will remain frozen

or be used for research and/or be destroyed. FitzPatrick’s argument stating a difference in

intention and foreseeability between spare embryos and research embryos is thus incoherent. In

standard IVF practices, embryos are created and destroyed (or at best remain frozen) in the same

constitutive relation as in creating embryos for research, only for a different purpose; decreasing

risks and increasing pregnancy chances for the woman. Therefore, double effect cannot be used

to argue for a moral difference in performing standard IVF practices leading to spare embryos

and creating embryos for research purposes.

How coherent is the set of moral principles identified in Devolder’s argument? According

to her, if we allow standard IVF practices, we should also allow the creation of embryos for

research (Devolder, 2005, 2013). This can be interpreted as an argument of overlapping

consensus, because the ground of justification is in this case the general acceptance of standard

IVF practices. In my view, she rightly argues that double effect cannot justify the creation of

spare embryos any more than research embryos, as I have shown this in the previous paragraphs.

According to Devolder, proponents of a moral distinction between the creation of spare embryos

and research embryos grant moral value to the whole group of early-stage embryos in the IVF

procedure (Devolder, 2005). This is precisely what happens when proponents of the moral

distinction argue that in IVF the instrumentalization of embryos is not hundred percent, as against

the hundred percent instrumentalization of research embryos. Indeed, one of the created embryos

for IVF will result in a child and might therefore be not instrumentally used. When you perceive

all the embryos as a group and the IVF cycle yields ten embryos, ninety percent of the embryos is

instrumentalized when one embryo results in a child. In a case of creating embryos solely for

research, one hundred percent of all embryos are instrumentalized. This is however incoherent

when you do not perceive early-stage embryos a group, but separately. An argument one could

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imagine is to say that one does not know beforehand which embryo will result in a child and

which embryos will end up being spare embryos in IVF. This way, all embryos at IVF have at

least a chance to become a child. However, this does not make any sense when we consider our

standard IVF practices. The fact that you do not know beforehand which one of the embryos is

going to result in a child does not mean that you then should ignore the fact that they are separate

entities, each of which has a similar chance of not being chosen for transfer to the women. In

playing Russian Roulette, the person who gets the bullet is not only instrumentalized for 16,67

percent (one out of six) to save the other players. The fact is, as Devolder correctly explains

(Devolder, 2005), the embryos that remain unused after IVF, are fully instrumentalized individual

entities. Moreover, the fact that some embryos will be chosen for transfer, does not detract from

the fact that they were not created with the intention that these specific embryos would indeed be

allowed to grow into a child. Even the embryo resulting in a child could be perceived as

instrumentalized. The fact that it is not known beforehand which embryo will result in a child,

means that every embryo is instrumentally used to provide the ability to choose one out of them. I

conclude that the creation of embryos in standard IVF is no less instrumentalizing than the

creation of embryos for research.

The instrumentalization of embryos in standard IVF practices as well as of embryos

created for research can thus be considered equal. However, how strong is Devolder’s argument

that because embryos are instrumentalized in standard IVF, it should also be accepted to

instrumentalize embryos by creating them for research? In the light of health risks for the woman

and success rates of pregnancy, woman-friendly IVF is the current standard procedure in IVF.

This means that by performing woman-friendly IVF instead of embryo-friendly IVF, we imply

that the creation of spare embryos is proportionate to the benefits for the woman. To say that a

certain action is morally right because it is proportionate to the benefits means that this action

meets the proportionality principle. I will explain this principle more extensive in the last part of

this section. As for now, I will leave it to the explanation I just gave.

Devolder, rightly argues that in woman-friendly IVF, the proportionality principle can

only be met when the value of the embryo is considered rather low (Devolder, 2013). To accept

the creation and destruction of spare embryos in order to benefit the health of the woman, means

that the embryo cannot be considered to have full moral status. Otherwise, the health benefit for

the woman would not be proportionate to the deaths of the embryos. I have already argued above

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that the middle view, granting a limited moral value to embryos, is coherent with the background

theories of personhood and potentiality. The rather low value of the embryo described by

Devolder is thus coherent with the overall principles and theories. According to Devolder,

because the creation and instrumentalization of spare embryos is justified in IVF because of the

benefits for the woman, the creation and instrumentalization of embryos for research can also be

justified because of the benefits regarding safety and effectiveness of important ARTs (Devolder,

2005). In other words; if the moral value of the embryo is considered rather low in IVF

procedures, its low moral value should not stand in the way in performing important research.

Although Devolder succeeds to invalidate a difference in instrumentalization between spare

embryos and research embryos, she seems to overlook another difference in intention that can be

made by opponents of creating embryos for research. Devolder has shown that creating and

instrumentalizing spare embryos for standard IVF is accepted because of the rather low moral

status of embryos. However, is there not a difference in using embryos to benefit a reproductive

purpose against using embryos to benefit research purposes? Before I will turn to this question, I

will first discuss the last set of principles.

The last set of moral principles I assess is extracted from the argument of Brock. His

argument states that neither the creation of an embryo, not its use and destruction, is bad or

impermissible and therefore, the combination of the three elements should not be morally

problematic either (Brock, 2010). The moral principle that can be extracted from this reasoning

(if one action is considered justifiable and another action is considered justifiable, the

combination of them should also be considered justifiable) does not succeed in invalidating

double effect reasoning, because Brock’s argument completely overlooks the intention argument.

In his argument, he implies that the intention of an action does not matter, while the intention is

exactly the combining factor between creating embryos and using and destroying embryos. The

act of creating embryos solely for the use and destruction in research is argued to be morally

impermissible because opponents argue that it is wrong to create embryos with the intention of

destroying them. They argue for a difference in intention between creating spare embryos and

research embryos using double effect. By ignoring the fact that the intention of creating research

embryos is the reason why the combination of the three elements (creation, use and destruction)

is perceived as morally problematic, Brock does not overcome double effect reasoning.

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Thus far I have shown that it is incoherent to argue for a difference in instrumentalization

between spare embryos and research embryos. I have also shown that double effect is as

incapable of justifying the creation of spare embryos in women-friendly IVF as it is with regard

to the creation of embryos for research. In the creation of spare embryos and the creation of

research embryos, the embryo deaths are intended and not merely foreseen. Does this mean that

the intention argument is made invalid?

An argument I have not yet discussed, is the argument that the instrumental use of

embryos for reproductive purposes is different than the instrumental use for research purposes.

Creating embryos to benefit a reproductive purpose, might still be connected to the ‘natural’,

original purpose of embryos, whereas the creation of embryos to benefit research purposes lacks

this connection. However, as already been argued in the paragraph assessing the coherency of

van Beers’ argument, creating embryos for research on ARTs also benefits reproductive

purposes. This means that the embryos created for research are still connected to a ‘natural

purpose’ to a certain degree. Nevertheless, it must be admitted that this connection is more

indirect than in the case of standard IVF. Furthermore, this only counts for the creation of

embryos for ARTs.

The argument considering a so-called ‘natural’ purpose also leads to another possible

argument against the creation and instrumentalization of embryos for research; the slippery-slope

argument. If we allow the creation and instrumentalization of embryos for research, this might

lead to a slippery slope towards possibly dangerous and dehumanizing (unnatural) practices.

Examples of such practices could be the use of fetuses for spare parts, cloning babies or the

creation of designer babies.

The slippery-slope argument raises legitimate concerns, but the possibility that the

creation of embryos for research will lead to dangerous and dehumanizing practices is very

unlikely. Several dehumanizing practices, such as the creation of embryos for body parts, can be

prevented by a simple ban on reproductive cloning and other relevant regulations that are already

in force in many countries (Sandel, 2004). For instance, in the Netherlands, it is already included

in the law that when the ban on the creation of embryos for research would end, article 9 and 11

of the embryo law, stating that cloning and other dehumanizing purposes will not be allowed, will

come into force (CBO, 2003). Moreover, the criteria of proportionality and subsidiarity (laid

down in the treaty on European Union) have to be met in every case where embryos would be

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created for research purposes (de Wert & Dondorp, 2008). With the proper regulation, it is thus

very unlikely that allowing the creation of embryos for research will lead to a slippery slope of

dangerous dehumanizing practices with embryos.

5.2.5. The ethics of obtaining egg cells to create embryos for research

The second argument against the ethical justifiability of creating embryos for research concerns

the oocyte donors. To assess these arguments, I include practice-based intuitions supported by

different researches. Although the concerns should be taken very seriously in the debate on

research embryos, it has been argued that the risks for egg cell donors are not as big as often is

suggested (Olsthoorn-Heim et al., 2006). Considering the practical risks for egg cell donors,

ovarian hyper stimulation syndrome (the biggest risk of hormone stimulation) has been

associated with the emergence of a pregnancy (Devroey et al., 2011; Mertes & Pennings, 2011).

This means that women who donate their egg cells outside a reproductive procedure are less

likely to being at risk. As to the social risks, several legal conditions for egg cell donation prevent

the possible exploitation of women. An example of such condition is that women are not allowed

to be paid for their donated egg cells (Olsthoorn-Heim et al., 2006). If egg cell donation would

have financial benefits, it is not unthinkable that this could lead to the exploitation of women in a

precarious financial situation (Baylis, 2000; Rao, 2006). In such a case, women of a lower

economic status could be persuaded to collaborate in egg cell donation, because they might be in

desperate need of money. These women would then be more vulnerable for exploitation than

women with a higher income. This does not only lead to inequality between more and less

wealthy people, but it also threatens these women’s autonomy.

Although the medical and social risks are not as big as often suggested, this does not

mean that we should not pay attention to them. It stays important to include the risk of coercion

and exploitation of women in the debate of creating embryos for research. To assume that a

situation so closely connected to potential violation of the rights of women does not need

constant check-up would be naïve and ignorant. The creation of embryos for research can thus

only be justified when taking the potential risks for egg cell donors into constant consideration.

This means that to allow the creation of embryos for research, there should be proper regulation

regarding the responsible obtainment of egg cells.

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One suggestion to responsibly obtain a sufficient amount of egg cells for research is the

initiative of egg sharing (Ahuja, Simons, & Edwards, 1999; Blyth, 2002). Egg sharing is “an

arrangement in which a woman is offered free or reduced-cost assisted conception treatment in

return for ‘donating’ oocytes for the treatment of another woman or for research, the cost of her

treatment being subsidized by the recipient of her oocytes” (Blyth, 2002). Instead of paying

women for their donation, the donor receives free or reduced-cost reproductive treatment, such as

IVF. During the reproductive treatment, already several mature egg cells will be produced in

standard IVF. In egg sharing, a couple of these egg cells will be donated. This initiative may still

come with increased medical risks for women, since the arrangement to donate some of the

woman’s oocytes may entail that more often a further stimulation cycle is necessary than would

be the case if the woman could use all oocytes obtained in one cycle to create embryos for

herself. Moreover, egg sharing can still lead to exploitation since it is thinkable that only women

of a lower income will participate because of the high treatment costs in countries or settings

where IVF Is not reimbursed. However, egg sharing rules out the possibility to sell gametes to

earn money. Furthermore, research has shown that women participating in egg sharing

acknowledge the demand of egg cells can be exploitive, but emphasize that they make an own

decision to volunteer for egg sharing (Haimes, Taylor, & Turkmendag, 2012). These women

argue that they have the ability to act autonomously in their decision to volunteer. Nonetheless, as

these women still make a decision under (financial) circumstances not necessarily of their

choosing, egg sharing can only diminish, but not rule out all risks for women. Therefore, it is key

to make sure the risks of obtaining egg cells are always proportionate to its benefits.

5.2.6. Subsidiarity and proportionality

I have argued that if we accept the use of embryos for the purpose of maximizing success and

safety for woman during IVF, we could also accept the creation of embryos for important

research purposes. This does not mean that we can freely create embryos for research without any

constraint. How to decide in which cases it can be justified to create embryos for research? To

constantly reflect on the possible risks for egg cell donors is one example of a condition we have

to meet. Moreover, focusing on the limited moral value of the early-stage embryos and the risks

towards egg cell donors, one can identify two conditions which have to be met to justify the

creation of embryos for research.

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The first condition is to meet the subsidiarity principle, which states that the creation of

embryos for research is only permissible when the research cannot be performed in an alternative

(suitable) way to reach the same goal (Isasi & Knoppers, 2006). To give an example, the creation

of embryos for the purpose of research can only be justified when the same research cannot be

performed with spare embryos or without any kind of embryos. It could be the case that there are

no spare embryos available, that the research in question can only be performed with specially

created embryos, or that research with e.g. animal models cannot give the same important

information. In all cases, there is no adequate alternative research methodology to perform the

needed research, which means the creation of embryos for research can be justified according the

subsidiarity principle.

Second, research embryos should not be created for every arbitrary purpose. Creating and

destroying embryos for research on e.g. cosmetics would not commensurate to the specific

respect they deserve. However, if the destruction of embryos serves a morally important purpose,

their social respect and limited moral status are not violated (Brock, 2010). To decide which

research is ‘important enough’ to be balanced against the costs of creating end destructing

embryos, research has to meet the so called ‘proportionality principle’. In the case of embryo

research, the proportionality principle refers to “constraining embryo research to practices that

serve important and worthwhile goals and purposes” (Isasi & Knoppers, 2006). This means that

the study using research embryos should be likely to yield important scientific or clinical data

(ASRM, 2014), such as research results concerning the treatment and prevention of serious

human disease and suffering (Brock, 2010). Also considering proportionality, the creation of

research embryos should be performed with the minimum required gametes or embryos for

adequate research and minimal risks for gamete donors (ASRM, 2014).

5.3. The case study: SCD Gametes

I have argued that the creation of embryos for research can be justified under certain

circumstances. I have identified two conditions for justifying the creation of embryos for

research. Clearly, the creation of embryos cannot be justified for every arbitrary goal and in any

arbitrary study plan. To illustrate how to decide if the creation of embryos for a certain study can

be justified, I will perform a case study on embryo research on the safety and effectiveness of

using SCD gametes. Thus; can the creation of embryos for research be justified for research

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aimed to preclinically investigate the safety and effectiveness of reproduction using SCD

Gametes?

5.3.1. Subsidiarity

The first principle that has to be met is the principle of subsidiarity. I argue that there are two

approaches of subsidiarity.

The first approach questions if the research can be performed in an alternative effective

way. I have already explained that embryo research on SCD gametes cannot be performed with

spare embryos. The embryos to be investigated need to be created using both naturally derived

and either SCD sperm or oocytes. There is thus no alternative for performing embryo research

into the safety and effectiveness of SCD gametes than by creating embryos. It can also be

questioned if there are possibilities to do sufficient safety research on artificial gametes without

performing embryo research. Animal research and preclinical studies can also provide

information on the effectiveness and safety of SCD Gametes. However, as I already have argued

in chapter two and three (pages 21-42), embryo research forms an important step between using

the technique on animals and using it on born human individuals, by giving essential information

on the development of the embryo created by this technique (Brison et al., 2013; Dondorp & de

Wert, 2007, 2011; Hinxton, 2008). This means that there is no adequate alternative to perform the

same important research in another way.

The second approach questions if the goal of the SCD gametes can be reached in an

alternative way. Are there other options to help couples with reproduction? Adoption or the use

of donor gametes can also help couples that face infertility problems to get a child. However, the

difference between adoption or the use of donor gametes and using SCD gametes is the fact that

the future child can only be genetically related to both parents in the latter case. Currently, there

is no alternative for couples facing infertility problems to create a genetically related child. This

means that it should be investigated if the benefit of creating a genetically related child can be

balanced against the cost of creating embryos for research. This will be discussed in the section

beneath, considering proportionality.

Since there are no alternative adequate research methodologies to perform research on

SCD Gametes or to get a biologically related child with other reproductive options, the creation

of embryos for research on SCD gametes can be justified following the principle of subsidiarity.

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5.3.2. Proportionality

The second principle questions if the benefits of SCD gametes and embryo research on SCD

gametes are big enough to justify the creation of research embryos? I argue that there are also two

approaches of proportionality.

The first approach questions if the importance of SCD gametes is proportionate to the

creation of research embryos. As I already explained above, the difference between the use of

SCD gametes and other reproductive alternatives is the possibility to have a genetic link between

parents and child. The fact that there are no alternative ways for infertile couples to get a

biologically related child is enough to meet the subsidiarity principle. To meet the proportionality

principle however, it has to be shown that the importance of the genetic link is proportionate to

harms of the creation of embryos. This means that to justify the creation of embryos for research

on SCD gametes, it is key to investigate the importance of the genetic link.

Although the importance of the genetic link needs further scrutiny and several researches

have suggested that there are no significant differences considering psychological well-being

between biologically and socially related parents and children (Golombok et al., 2004; Golombok

et al., 2006; Lansford, Ceballo, Abbey, & Stewart, 2001), it appears in reality that parents as well

as children consider the genetic link to be very important (Mertes & Pennings, 2010). The

importance of the genetic link for parents appears in the fact that couples cooperate in invasive

ART treatments like IVF and ICSI, when they could also choose for alternatives such as the

adoption of a child. To give an example, ICSI holds a “statistically significantly higher risk of

malformations for the offspring than natural conception. Still the overwhelming majority of

patients opt for this technique” (Mertes & Pennings, 2010, p. 270). Furthermore, the decision to

choose for donor conception is also often made after a long process of failed ART treatments.

This implies that the treatments offering a genetic link between parents and child are generally

favored in comparison to options without a genetic link. As to the child, it is very common that a

child created with a donor gamete, or a child that has been adopted, wants to meet his or her

biological parent(s). This means that the child apparently sees value in the biological link

between him or her and the biological parents. The importance of the genetic link can thus not be

found in studies regarding psychological well-being of genetically related parents and children,

but in the fact that many parents and children consider this link to be valuable. The question is

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then; is the desire of parents to have a genetically related child important enough to justify the

creation of embryos for safety research?

Furthermore, after the safety and effectiveness of SCD gametes are established, SCD

gametes can be used to decrease the need of oocyte donors. Using the technique to develop SCD

gametes makes it possible to derive gametes out of stem cells. This way, there can be created egg

cells and sperm cells in the amount we need for research or therapy, which means that the

pressure on gamete donors would decrease remarkably. Additionally, the method can improve the

safety of current IVF practices, by making hormone stimulation redundant.

As to the second approach, is the importance of embryo research on SCD gametes

proportionate to the creation of research embryos? As already explained under the principle of

subsidiarity, embryo research is considered an important contribution to the research process. The

question then remains; is the extra safety proportionate to the creation and destruction of

embryos? I have already argued that embryos have a limited worth of value, and that if they are

used in IVF to maximize pregnancy chances and lowering risks for women, the moral value of

the embryo is also proportionate to use it in important research. If embryo research would be left

out of the research process, this means that the use of SCD gametes would be tested from animal

models directly to humans in clinical trials. Considering the full moral status of born human

individuals as against the limited moral status of early-stage embryos, the use of embryos for

research to prevent exposing the unknown risks to born human individuals can be perceived as

proportionate.

Aditionally, it has been argued that SCD gametes can help in fundamental research to

understand the development of sperm- and egg cells and of early embryos (Hinxton, 2008;

ZonMw, 2012). Therefore, the embryo research is not only benefitical towards a responsible safe

introduction of SCD gametes, but also benefits fundamental research.

In the light of the assumption that the genetic link is of moral importance and the benefits

considering oocyte donors, the improvement of IVF and safety, the creation of embryo for

research on SCD gametes meets the proportionality principle. To perform the creation and

research of embryos in a responsible, respectful and proportionate way, I want to emphasize that

it is important to use a minimal amount of embryos and donor gametes to perform adequate

research. In conclusion, by meeting the subsidiarity principle as well as the proportionality

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principle, the creation of embryos for safety research concerning the responsible introduction of

SCD gametes into clinical practice can be justified.

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In this thesis, I investigated if the creation of embryos for safety research can be ethically

justified, in particular on safety research concerning the responsible introduction of SCD gametes

into clinical practice, and under what conditions.

6.1. Results

I have argued that many ARTs are introduced into clinical practice without sufficient safety

research. Several authors have pointed out that all too often, the introduction of new ARTs has in

the past taken place on a trial and error basis (Brison et al., 2013; Dondorp & de Wert, 2011;

Harper et al., 2012; Pennings et al., 2007; Provoost et al., 2014). I have shown that IVF as well as

ICSI lacked sufficient safety and effectiveness research and were merely introduced on a trial-

and-error basis (Dondorp & de Wert, 2011). The introduction of ARTs into clinical practice

without proper research is not only a matter of the past. The fact that there was no to little

preclinical testing before introducing the mitochondrial supplementation treatment ‘Augment’

into clinical practice is a recent illustration of the point.

In the light of the health interests of children conceived through these technologies, as

well as of the health interests of the parents, current safety research should be improved

(Dondorp & de Wert, 2011; Harper et al., 2012; Pennings et al., 2007). The Task Force on Ethics

and Law of the European Society of Human Reproduction and Embryology (ESHRE) argued that

sufficient safety research should be performed to serve both the welfare of the child and public

health, and to inform potential parents (Pennings et al., 2007). ESHRE recommends formal

research divided into four steps; a) animal studies, b) preclinical embryo research, c) clinical

trials and d) follow-up studies (Pennings et al., 2007). The American College of Obstetricians and

Gynecologists (ACOG) supports the necessity for safety and effectiveness research. According to

them, the risks of ARTs should be properly investigated because of the right on informed consent

for the patients and adequate information for clinicians (ACOG, 2006a). The American Society

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for Reproductive Medicine (ASRM) adds with regard to embryo- and gamete research that such

research always has to meet certain conditions, such as the importance of the goal of the study

and the necessity for approval by an ethics committee (ASRM, 2014).

Although there are several good recommendations on how to safely introduce new ARTs

(ACOG, 2006a; ASRM, 2014; Pennings et al., 2007), these are often not followed in practice. As

seen in the introduction of Augment treatment, new technologies are despite of all the

recommendations still introduced into clinical practice without sufficient evidence of safety and

effectiveness. This means that introducing new ARTs in clinical practice with the current way of

safety research procedures would be irresponsible. Therefore, current research practice should be

improved. This concerns also the safety research for the responsible introduction for SCD

gametes in specific.

Thereafter, I have shown that the creation of SCD gametes is an emerging development in

the field of ART. Although the development is still at a research stage, current research suggests

medically assisted reproduction using SCD-gametes is a possible scenario (particularly for

couples currently dependent on donor gametes for reproduction) in the near to midterm future

(Hinxton, 2008; Marques-Mari et al., 2009).

As a new technique in ART, SCD gametes can have many applications. One can think of

SCD Gametes as a fertility treatment for infertile or subfertile couples or post-menopausal

women, but they could also potentially help transsexuals, intersexual persons and gay couples

with reproduction. Furthermore, in addition to reproductive goals, SCD gametes can be useful in

research. It has been argued that SCD gametes can help in fundamental research to understand

the development of sperm- and egg cells and of early embryos (Hinxton, 2008; ZonMw, 2012).

Moreover, the possibility to create gametes out of stem cells decreases the need for gamete

donors for research and therapy and can also make hormone stimulation redundant in IVF

treatment.

In an environment where ARTs are often introduced without sufficient safety research,

the possible introduction of SCD gametes in medically assisted reproduction raises the question

how this should be safely performed. A process of animal research, preclinical embryo research,

clinical trial and follow-up studies is recommended to investigate the safety and effectiveness

ARTs, and specifically of SCD gametes (Brison et al., 2013; Dondorp & de Wert, 2007, 2011;

Hinxton, 2008). Embryo research is a very important step in the process, because it can provide

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essential information on the development of the embryo created using a certain ART (Brison et

al., 2013). In most cases of research on ARTs, spare embryos left over from IVF can be used for

preclinical embryo research. However, research on the safety of SCD gametes needs to be

performed with specially created research embryos. The use of specifically created embryos for

research is however regarded as morally problematic, because of concerns on the moral status or

value of embryos and/or to the risk that women will be pressured into donating oocytes against

their best interest.

In chapter four, I mapped the ethical debate, identified in the selected literature,

concerning the use and creation of embryos for research. I argued that this debate can be

structured around three main ethical issues. First, there is the question if embryos can be used for

research in general. This is closely connected to the moral status we describe to the embryo. I

have argued that there can be distinguished three different views on this. Proponents of the first

view considers embryos to have the same moral value as grown human individuals. According to

this view, it cannot be ethically justified to use embryos for research. Proponents of the second

view consider embryos to have the same value as any other body tissue. They are not opposed to

the use of embryos for research any more than to the use of any other body tissue for research.

The third view, inhabiting the middle position, states that embryos have a limited worth of

protection. They grant limited moral value to the embryo because it can potentially grow into a

human being or because of its symbolic connection with mankind. Their moral value is not as

high as it is for grown human individuals, but also not as low as for any body tissue. People

supporting this view grant a moral value to the embryo which increases the more the embryo

develops. Following this view, the use of embryos for research can be justified when the research

is commensurable to the limited value of the embryo.

Supporters of the first view clearly forbid the creation of embryos for research and

supporters of the second view clearly would not mind creating embryos for research. The middle

ground, which is supported by the majority, leaves room for discussion. Opponents of the

creation of embryos for research argue that such practices instrumentalize embryos because of a

difference in intention between creating spare embryos and research embryos (van Beers, 2016).

Using double effect reasoning, the opponents argue that in IVF, spare embryos are created as a

foreseen side effect of the procedure, whereas research embryos are intentionally created for

research and thus for their destruction (FitzPatrick, 2003; Murphy, 2012). Proponents of the

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creation of embryos for research argue that double effect reasoning cannot offer a moral

distinction between the creation of spare embryos and research embryos, because in current IVF

practices, spare embryos are created with the same instrumentalization as research embryos

(Devolder, 2005). In accepting current IVF practices leading to spare embryos, the moral status

of the embryo must be considered that low that it should also be accepted to create embryos for

research (Devolder, 2013). It has also been argued that the creation as well as the use and

destruction of embryos is separately justified, which means that the combination of the three

elements should also be justifiable (Brock, 2010).

Another problem that rises with the creation of embryos for safety research is the demand

for donor egg cells. In IVF practices, the benefit for the women undergoing these procedures is

clear. The risks are accepted, because the treatment can help to pursue the reproductive goal of

the women. In donating for research however, women undergo hormone stimulation therapy and

invasive medical procedures, when there is no concrete benefit for the woman (Baylis, 2000;

Gerrand, 1993). In egg cell donation, women are exposed to medical and social problems;

practical, because of the hormone therapy and invasive IVF procedure without knowing the risks,

and social, because of a potential exploitation of women. Both medical and social problems

threaten women’s autonomy in making informed and voluntary choices (Gerrand, 1993). By

threatening the autonomy of women potentially participating in egg donation, without any

physical, personal, or financial benefits, the risk of coercion and exploitation of women should be

properly addressed in the discussion on research embryos (Baylis, 2000; Gerrand, 1993).

In chapter five, I first assessed the moral acceptability of using (spare) embryos and

creating embryos for research in general, using the method of WRE. I identified three sets of

principles considering the use of embryos for research and identified four different sets of

principles considering the creation of embryos for research, based on the arguments of several

authors. I argued that the middle position, granting a limited moral value and limited degree of

protection to embryos, is coherent with the background theories of personhood and potentiality as

well as with the widely held intuition that embryos have some (intrinsic or symbolic) value.

Because early-stage embryos cannot be considered persons, they do not deserve full moral status.

Yet, to respect their potentiality to grow into human beings and their social connection to the

human species, they deserve more protection than any other body tissue. This means that their

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moral status is located between full and no moral status, and thus deserve a limited degree of

protection.

Thereafter, I have shown that the moral sets of principles found in the arguments of

several authors are incoherent with the background theories of double effect and instrumental

value (Brock, 2010; FitzPatrick, 2003; Murphy, 2012; van Beers, 2016). Both theories cannot

serve as a foundation for a moral distinction between spare embryos and research embryos. The

moral set of principles identified in the argument of Devolder (Devolder, 2005, 2013) fit best to

the background theories, but still fails to convince that creating embryos to benefit research

purposes is morally similar to creating embryos to benefit reproductive purposes. I explained one

could argue that to create embryos for reproductive purposes is commensurable to the ‘natural’

aim of creating embryos, but the creation for research purposes can be perceived as indirectly

supporting reproductive purposes as well. Last, the idea that creating embryos for research leads

to a slippery slope of dangerous and dehumanizing practices is very unlikely, because of

governmental regulation.

Additionally, although the concern that the creation of embryos for research leads to the

exploitation of women should be taken very seriously, the risk of exploitation can be diminished

by proper regulation as well. An example I have given of a possibility of a practice in which

oocytes can be obtained against acceptable risks for egg cell donors is the egg sharing initiative

(Blyth, 2002; Haimes et al., 2012).

Thereafter, I have argued that to decide if specific research can be balanced against the

harm of creating and destructing embryos and the risks for egg cell donors, research should meet

the principles of subsidiarity and proportionality. In the case study on SCD Gametes, I studied the

ethical justifiability of embryo research on SCD gametes. The question I posed was; if the use

and creation of embryos for research can be justified under specific circumstances, can it also be

justified for research on SCD Gametes? I argued that research concerning the responsible

introduction of SCD gametes into clinical practice does meet the principles of subsidiarity and

proportionality. Since there are no alternative adequate research methodologies to perform

research on SCD Gametes or to get a biologically related child with other reproductive options,

the creation of embryos for research on SCD gametes can be justified following the principle of

subsidiarity. Furthermore, I have shown that as to research and therapeutic purposes, the research

on SCD gametes meets the proportionality principle. Could SCD gametes be introduced into

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clinical practice after proper research, egg cells could be easily created so that enough egg cells

are available for research and therapy. This means that the demand for egg cell donors will

increase significantly. Additionally, the creation of SCD gametes makes the use of hormone

stimulation in reproductive treatments like IVF redundant. As to the reproductive purposes of

SCD Gametes, to meet the proportionality principle, it is important to further investigate whether

the importance of the genetic link is proportionate to the harms of the creation of embryos and

risks to egg cell donors.

6.2. Strengths and limitations

A strength of this thesis is that it provides an ethical framework to assess the acceptability of the

creation of embryos for research in the broad field of ARTs. This makes this thesis relevant to

questions that consider the justification of embryo research on contemporary, but also on future

emerging ARTs. Furthermore, the ethical assessment on the creation of embryos for research

provides insights not only applicable on ARTs, but also on other bioethical issues, such as stem

cell research. Additionally, the case study on SCD gametes provides an example of how the

principles of subsidiarity and proportionality can be used as criteria for justification on the

creation embryos for specific research purposes.

A limitation of the thesis is that the discussed ethical debate mainly focuses on a practical

ethics approach. This means that other approaches that can also give insights in the justifiability

of the creation of embryos for research, such as virtue ethics, feminism or mediation theory have

not been taken into account. Although this thesis can give insights in the niche of practical

biomedical ethics, I do not claim to cover all possible approaches to the ethical issues presented

in this thesis.

The strength of using WRE in this thesis is that it enabled me to identify relevant

background theories behind moral intuitions and principles. In this case, I discovered that the

different views on the moral status of the embryo were based on the theories of personhood and

potentiality. Also the arguments considering the moral difference between spare embryos and

research embryos were based on background theories; double effect and instrumental value.

These theories formed a moral framework, in which the moral principles could be assessed.

Within the moral framework of relevant background theories and current moral intuitions and

principles, I have shown that the creation of embryos can be justified.

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A limitation of WRE is that it can only provide justification within a specific framework.

Although WRE can shed light on where it is that opposing moral judgements and principles

conflict, it cannot provide an absolute justification. In the case of embryo research, WRE showed

that the third view, stating that embryos have a limited degree of value, is coherent with the

theories of personhood and potentiality. However, it is possible that other alternative parties

disagree on the current content of these theories. The Catholic Church for instance, disagrees at

many points with the current concept of personhood. WRE thus illustrates where the problem of

two views collapsing lies (in this case in the concept of personhood), but still does not enable me

to say that one moral position is true and another is not. WRE thus only provides justification

within a certain framework, but cannot give conclusions concerning truth.

6.3. Recommendations

In the case study of this thesis, I investigated if the creation of embryos for research on SCD

Gametes can be justified under the principles of subsidiarity and proportionality. To meet both

principles, it is important to have relevant literature. In performing the assessment, there appeared

a gap in the literature considering the reproductive benefits of SCD gametes and considering

embryo research on SCD gametes specifically. Therefore, it is important to expand current

literature.

Although SCD Gametes can provide benefits in research and therapy and improve other

reproductive technologies such as IVF, the specific benefit for clinical application for

reproductive purposes remains unclear. One specific gap in the literature is research on the moral

importance of the genetic link between parents and children. Although research has provided

intuitive arguments on the importance of the genetic link (Mertes & Pennings, 2010), the topic

needs further scrutiny. Therefore, I recommend further research on the topic of the importance of

the genetic link between parents and child. If the genetic link would appear as important as

suggested, it would enable a stronger position in meeting the principle of proportionality.

One approach to justify the creation of embryos for research on SCD gametes is to argue

from a reproductive autonomy perspective. Instead of arguing for an objective moral importance

of the genetic link, this approach argues for subjective autonomy. If the genetic link cannot be

proven objectively morally important, is not the reason that some parents strongly prefer a

genetic link enough to meet the proportionality principle? Since more research on the benefits of

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SCD gametes against other reproductive technologies is needed, I recommend to investigate the

argument of reproductive autonomy concerning the importance of a genetic link.

As a last recommendation, research specifically on the effectiveness of embryo research

on SCD gametes is lacking. Although many researchers have argued that embryo research

improves research on ARTs (Brison et al., 2013; Dondorp & de Wert, 2011; Pennings et al.,

2007), research on the effectiveness of preclinical embryo research on SCD gametes is too

limited. This has probably to do with the fact that the creation of SCD gametes is still at a highly

experimental stage. However, since preclinical embryo research can only be justified under the

condition that it can provide additional safety information that would reduce the gap between

animal studies and clinical application, the effectiveness of preclinical embryo research on SCD

gametes should be further investigated.

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ACOG. (2006a). Innovative practice. Obstetrics and Gynecology, 108(6), 1589-1595. ACOG. (2006b). Using Preimplantation Embryos for Research. Obstetrics and Gynecology, 108, 1305-1317. Ahuja, K., Simons, E., & Edwards, R. (1999). Money, morals and medical risks: conflicting notions underlying the

recruitment of egg donors. Human Reproduction, 14(2), 279-284. Aquinas, T. (1981). Summa theologiae, trans. New York: English Dominicans. Arditti, R., Klein, R. D., & Minden, S. (1984). Test Tube Women: What Future for Motherhood? ASRM. (2014). Informed consent and the use of gametes and embryos for research: a committee opinion. Fertility

and Sterility, 101(2), 332-335. Baker, L. R. (2000). Persons and bodies: A constitution view: Cambridge University Press. Barberi, T., Klivenyi, P., Calingasan, N. Y., Lee, H., Kawamata, H., Loonam, K., . . . Topf, N. (2003). Neural subtype

specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice. Nature biotechnology, 21(10), 1200-1207.

Baylis, F. (2000). Our cells/ourselves: creating human embryos for stem cell research. Women's Health Issues, 10(3), 140-145.

Beeson, D., & Lippman, A. (2006). Egg harvesting for stem cell research: medical risks and ethical problems. Reproductive Biomedicine Online, 13(4), 573-579.

Bennett, J. (1966). 'Whatever the Consequences'. Analysis, 26(3), 83-102. Blyth, E. (2002). Subsidized IVF: the development of ‘egg sharing’in the UK. Human Reproduction, 17(12), 3254-

3259. Boyle, J. M. (1980). Toward understanding the principle of double effect. Ethics, 90(4), 527-538. Brison, D. R., Roberts, S. A., & Kimber, S. J. (2013). How should we assess the safety of IVF technologies?

Reproductive Biomedicine Online, 27(6), 710-721. doi:10.1016/j.rbmo.2013.09.006 Brock, D. W. (2010). Creating embryos for use in stem cell research. The Journal of Law, Medicine & Ethics, 38(2),

229-237. Buckle, S. (1988). Arguing from potential. Bioethics, 2(3), 227-253. Byrne, J., Pedersen, D., Clepper, L., Nelson, M., Sanger, W., Gokhale, S., . . . Mitalipov, S. (2007). Producing primate

embryonic stem cells by somatic cell nuclear transfer. Nature, 450(7168). Cagnone, G. L., Tsai, T. S., Makanji, Y., Matthews, P., Gould, J., Bonkowski, M. S., . . . John, J. C. (2016). Restoration

of normal embryogenesis by mitochondrial supplementation in pig oocytes exhibiting mitochondrial DNA deficiency. Scientific Reports, 6(23229), 1-15. doi:10.1038/srep23229

Cavanaugh, T. (2007). Double Effect Reasoning: Doing Good and Avoiding Evil. Journal of Military Ethics, 6(3), 255. CBO. (2003). Modelreglement Embryowet. Alphen aan de Rijn Van Zuiden Communications CDA. (1988). Zinvol Leven: Een christen-democratische bijdrage aan de discussie over draagmoederschap,

kunstmatige inseminatie, gift en in vitro fertilisatie Retrieved from Deventer: Chason, R. J., Csokmay, J., Segars, J. H., DeCherney, A. H., & Armant, D. R. (2011). Environmental and epigenetic

effects upon preimplantation embryo metabolism and development. Trends in Endocrinology & Metabolism, 22(10), 412-420.

Cohen, J., Scott, R., Alikani, M., Schimmel, T., Munne, S., Levron, J., . . . Willadsen, S. (1998). Ooplasmic transfer in mature human oocytes. Molecular Human Reproduction, 4(3), 269–280.

Cohen, S. M. (2016). Aristotle's Metaphysics. Retrieved from Stanford Encyclopedia of Philosophy website: http://plato.stanford.edu/entries/aristotle-metaphysics/#ActPot

Corea, B. (1985). The Mother Machine. New York: Harper and Row. Daniels, N. (1979). Wide reflective equilibrium and theory acceptance in ethics. The Journal of Philosophy, 76(5),

256-282. Daniels, N. (2011). Reflective equilibrium2016(7th of July). Retrieved from The Stanford Encyclopedia of Philosophy

website: http://plato.stanford.edu/entries/reflective-equilibrium/#WidRefEqu

94

De Rycke, M., Liebaers, I., & Van Steirteghem, A. (2002). Epigenetic risks related to assisted reproductive technologies: Risk analysis and epigenetic inheritance. Human Reproduction, 17(10), 2487–2494,.

de Sutter, P., Sermon, K., Goossens, E., Pennings, G., Bekaert, S., de Wert, G., & Dondorp, w. (2015). Science and Ethics of stem cell derived Gametes: IWT application for a SBO project with a primary societal finality. Universiteit Gent, Universitair Ziekenhuis Gent, Vrij Universiteit Brussel, Universitair Ziekenhuis Brussel, Maastricht University.

de Wert, G., & Dondorp, W. (2008). Burgerperspectieven op embryo onderzoek: Een gemiste kans. Tijdschrift voor gezondheidsrecht(4), 257-262.

DeGrazia, D. (1993). Equal consideration and unequal moral status. The Southern journal of philosophy, 31(1), 17-31.

DeGrazia, D. (1997). Great apes, dolphins, and the concept of personhood. The Southern journal of philosophy, 35(3), 301-320.

DeGrazia, D. (2008). Moral status as a matter of degree? The Southern journal of philosophy, 46(2), 181-198. Devolder, K. (2005). Human embryonic stem cell research: why the discarted-created-distinction cannot be based

on the potentiality argument. Bioethics, 19(2), 1467. Devolder, K. (2013). Embryo deaths in reproduction and embryo research: a reply to Murphy's double effect

argument. Journal of Medoical Ethics, 39(8), 533-536. doi:10.1136/medethics-2012-101065 Devroey, P., Polyzos, N. P., & Blockeel, C. (2011). An OHSS-Free Clinic by segmentation of IVF treatment. Human

Reproduction, 26(10), 2593-2597. Dickenson, D. (2002). Commodification of human tissue: implications for feminist and development ethics.

Developing World Bioethics, 2(1), 55-63. Donagan, A. (1979). The theory of morality: University of Chicago Press. Dondorp, W., & de Wert, G. (2007). On waving the embryos banner. Embryonic stem cell research and moral

reasoning in recent reports from the USA, the Netherlands and France. In J. Gunning & S. Holm (Eds.), Ethics, Law & Society (Vol. 3, pp. 7-24): Ashgate.

Dondorp, W., & de Wert, G. (2011). Innovative reproductive technologies: risks and responsibilities. Human Reproduction, 26(7), 1604-1608. doi:10.1093/humrep/der112

Doorn, N. (2011). Moral responsibility in R&D networks: A procedural approach to distributing responsibilities. (Doctoral thesis), TU Delft, Delft.

Eeuwijk, J., Kochems, K., van den Bosch, J., & Smilde-van den Doel, D. (2015). Onderzoek naar speciaal kweken. Retrieved from Pallas Health Research and Consultancy website: http://www.pallas-healthresearch.com/index.php?projecten_onderzoek

Eijk, W. J. (1997). Criteria voor de status van het menselijke embryo. . In E. W.J., J. Lelkens, P,M, , & P. Garrett (Eds.), Het embryo: iets of iemand? Oegstgeest: Colombia.

ESHRE. (2001). I. The moral status of the pre-implantation embryo ESHRE Task Force on Ethics and Law. Human Reproduction, 16(5), 1046-1048.

Fakih, M., Shmoury, M., Szeptycki, J., dela Cruz, D., Lux, C., Verjee, S., . . . Casper, R. (2015). The AUGMENT Treatment: Physician Reported Outcomes of the Initial Global Patient Experience. Journal of Fertilization: In Vitro - IVF-Worldwide, Reproductive Medicine, Genetics & Stem Cell Biology, 03(03). doi:10.4172/2375-4508.1000154

FitzPatrick, W. (2003). Surplus embryos, nonreproductive cloning, and the intend/foresee distinction. Hastings Center Report, 33(3), 29-36.

Foot, P. (1967). The problem of abortion and the doctrine of double effect. Oxford Review, 5, 5-15. Ford, N. M. (2002). The pregnant woman and her fetus. The Prenatal Person: Ethics from Conception to Birth, 75-99. Gerrand, N. (1993). Creating embryos for research. Journal of applied philosophy, 10(2), 175-187. Gezondheidsraad. (1996). ICSI. (1996/06). Den Haag. Gezondheidsraad. (1998). IVF: afrondende advisering Retrieved from Rijsewijk: Goldberg, J., Falcone, T., & Attaran, M. (2007). In vitro fertilization update. Cleveland Clinic Journal of Medicine,

74(5), 329-338. Golombok, S., Lycett, E., MacCallum, F., Jadva, V., Murray, C., Rust, J., . . . Margara, R. (2004). Parenting infants

conceived by gamete donation. Journal of Family Psychology, 18(3), 443.

95

Golombok, S., Murray, C., Jadva, V., Lycett, E., MacCallum, F., & Rust, J. (2006). Non-genetic and non-gestational parenthood: consequences for parent–child relationships and the psychological well-being of mothers, fathers and children at age 3. Human Reproduction, 21(7), 1918-1924.

Goto, K. (1993). Bovine microfertilization and embryo transfer. Molecular reproduction and development, 36(2), 288-290.

Grace, K. S., & Sinclair, K. D. (2009). Assisted reproductive technology, epigenetics, and long-term health: a developmental time bomb still ticking. Seminars in Reproductive Medicine, 27(5), 409-416. doi:10.1055/s-0029-1237429

Griesinger, G., Diedrich, K., Tarlatzis, B., & Kolibianakis, E. (2006). GnRH-antagonists in ovarian stimulation for IVF in patients with poor response to gonadotrophins, polycystic ovary syndrome, and risk of ovarian hyperstimulation: a meta-analysis. Reproductive Biomedicine Online, 13(5), 628-638.

Haimes, E., Taylor, K., & Turkmendag, I. (2012). Eggs, ethics and exploitation? Investigating women’s experiences of an egg sharing scheme. Sociology of health and illness, 34(8), 1199-1214.

Hansen, M., Bower, C., Milne, E., de Klerk, N., & Kurinczuk, J. J. (2005). Assisted reproductive technologies and the risk of birth defects-a systematic review. Human Reproduction, 20(2), 328-338. doi:10.1093/humrep/deh593

Harman, E. (1999). Creation ethics: The moral status of early fetuses and the ethics of abortion. Philosophy & public affairs, 28(4), 310-324.

Harman, E. (2003). The potentiality problem. Philosophical Studies, 114(1), 173-198. Harper, J., Magli, M. C., Lundin, K., Barratt, C. L., & Brison, D. (2012). When and how should new technology be

introduced into the IVF laboratory? Human Reproduction, 27(2), 303-313. doi:10.1093/humrep/der414 Harris, J. (1985). The value of life: an introduction to medical ethics. Abingdon: Routledge. Hayashi, K., Ogushi, S., Kurimoto, K., Shimamoto, S., Ohta, H., & Saitou, M. (2012). Offspring from oocytes derived

from in vitro primordial germ cell–like cells in mice. Science, 338, 971-975. Hayashi, K., Ohta, H., Kurimoto, K., Aramaki, S., & Saitou, M. (2011). Reconstitution of the mouse germ cell

specification pathway in culture by pluripotent stem cells. Cell, 146(4), 519-532. doi:10.1016/j.cell.2011.06.052

Hayashi, K., & Saitou, M. (2013). Generation of eggs from mouse embryonic stem cells and induced pluripotent stem cells. Nature protocols, 8(8), 1513-1524.

Hendriks, S., Dancet, E. A., van Pelt, A. M., Hamer, G., & Repping, S. (2015). Artificial gametes: a systematic review of biological progress towards clinical application. Hum Reprod Update, 21(3), 285-296. doi:10.1093/humupd/dmv001

HFEA. (2009). In vitro derived Gametes. Retrieved from http://www.hfea.gov.uk/in-vitro-derived-gametes.html Hinxton. (2008). The science, ethics and policy challenges of pluripotent stem cell-derived gametes. Retrieved from Hiramoto, Y. (1962). Microinjection of the live spermatozoa into sea urchin eggs. Experimental cell research, 27(3),

416-426. Hoedemaekers, R. (2003). Human embryos, human ingenuity, and government policy. Ethics & Medicine, 19(2), 75. Hyslop, L. A., Blakeley, P., Craven, L., Richardson, J., Fogarty, N. M., Fragouli, E., . . . Zhang, Q. (2016). Towards

clinical application of pronuclear transfer to prevent mitochondrial DNA disease. Nature. doi:10.1038/nature18303

Isasi, R. M., & Knoppers, B. M. (2006). Beyond the permissibility of embryonic and stem cell research: substantive requirements and procedural safeguards. Human Reproduction, 21(10), 2474-2481.

Jaworska, A. (2013). The Grounds of Moral Status2016(6h of July). Retrieved from Stanford Encyclopedia of Philosophy website: http://plato.stanford.edu/entries/grounds-moral-status/

Jochemsen, H., Garcia, E., Meir, A., & Harris, R. (2005). Human stem cells: Source of hope and of controversy: a study of human stem cell research and the patenting of related inventions. Chicago: The Bioethics Press,.

Johnson, M. H., Franklin, S. B., Cottingham, M., & Hopwood, N. (2010). Why the Medical Research Council refused Robert Edwards and Patrick Steptoe support for research on human conception in 1971. Human Reproduction, deq155.

Keefer, C. L. (1989). Fertilization by sperm injection in the rabbit. Gamete research, 22(1), 59-69. Kerkis, A., Fonseca, S. A., Serafim, R. C., Lavagnolli, T. M., Abdelmassih, S., Abdelmassih, R., & Kerkis, I. (2007). In

vitro differentiation of male mouse embryonic stem cells into both presumptive sperm cells and oocytes. Cloning and stem cells, 9(4), 535-548.

96

Korsgaard, C. M. (1983). Two distinctions in goodness. The Philosophical Review, 92(2), 169-195. Lansford, J. E., Ceballo, R., Abbey, A., & Stewart, A. J. (2001). Does family structure matter? A comparison of

adoptive, two‐parent biological, single‐mother, stepfather, and stepmother households. Journal of Marriage and family, 63(3), 840-851.

Lanza, R. P., Cibelli, J. B., & West, M. D. (1999). Human therapeutic cloning. Nature medicine, 5(9). Lanzendorf, S., Maloney, M., Veeck, L., Slusser, J., Hodgen, G., & Rosenwaks, Z. (1988). A preclinical evaluation of

pronuclear formation by microinjection of human spermatozoa into human oocytes. Fertility and Sterility, 49(5), 835-842.

Leridon, H. (2004). Can assisted reproduction technology compensate for the natural decline in fertility with age? A model assessment. Human Reproduction, 19(7), 1548-1553.

Loren, A. W., Mangu, P. B., Beck, L. N., Brennan, L., Magdalinski, A. J., Partridge, A. H., . . . Oktay, K. (2013). Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. Journal of Clinical Oncology, 31(19), 2500-2510.

Mangan, J. (1949). An Historical Analysis of the Principle of Double Effect. Theological Studies(10), 41-61. Marques-Mari, A., Lacham-Kaplan, O., Medrano, J., Pellicer, A., & Simón, C. (2009). Differentiation of germ cells and

gametes from stem cells. Human Reproduction Update, 15(3), 379–390. doi:10.1093/humupd/dmp001 Mathews, D. J., Donovan, P. J., Harris, J., Lovell-Badge, R., Savulescu, J., & Faden, R. (2009). Pluripotent stem cell-

derived gametes: truth and (potential) consequences. Cell Stem Cell, 5(1), 11-14. McIntyre, A. (2004). Doctrine of double effect2016. Retrieved from The Stanford Encyclopedia of Philosophy

website: http://plato.stanford.edu/entries/double-effect/ Mertes, H., & Pennings, G. (2010). Ethical aspects of the use of stem cell derived gametes for reproduction. Health

Care Analysis, 18(3), 267-278. Mertes, H., & Pennings, G. (2011). Ethical concerns eliminated: safer stimulation protocols and egg banking. The

American Journal of Bioethics, 11(9), 33-35. Molewijk, B., Stiggelbout, A. M., Otten, W., Dupuis, H. M., & Kievit, J. (2004). Scientific contribution. Empirical data

and moral theory. A plea for integrated empirical ethics. Medicine, Health Care and Philosophy, 7(1), 55-69.

Moran, D. (2009). The Phenomenology of Personhood: Charles Taylor and Edmund Husserl. MAYBELLE MARIE PADUA NOEL BEJO, 80.

Motluk, A. (2015). IVF booster offered in Canada but not US. Canadian Medical Association Journal, 187(3), E89-90. doi:10.1503/cmaj.109-4975

Murphy, T. F. (2012). Double-effect reasoning and the conception of human embryos. Journal of Medical Ethics, 39(8), 529-532. doi:10.1136/medethics-2012-100534

National Academies of Sciences Engineering and Medicine, N. ( 2016). Mitochondrial replacement techniques: Ethical, social, and policy considerations. (T. N. A. Press Ed.). Washington, DC: National Academies Press.

Newson, A., & Smajdor, A. (2005). Artificial gametes: new paths to parenthood? Journal of Medical Ethics, 31(3), 184-186.

Ng, R. K., & Gurdon, J. B. (2005). Epigenetic memory of active gene transcription is inherited through somatic cell nuclear transfer. Proceedings of the National Academy of Sciences of the United States of America, 102(6), 1957-1962.

Ng, S. C., Bongso, A., Ratnam, S., Sathananthan, H., Chan, C. K., Wong, P., . . . Goh, V. H. (1988). Pregnancy after transfer of sperm under zona. The Lancet, 332(8614), 790.

Olsthoorn-Heim, E., De Wert, G., Winter, H., te Braake, T., Heineman, M., Middelkamp, A., & Nierse, C. (2006). Evaluatie embryowet. Den Haag: ZonMw. Reeks evaluatie regelgeving: deel, 20.

OvaScience. (2016). Augment Treatment Retrieved from http://www.augmenttreatment.com/ Palermo, G., Joris, H., Devroey, P., & Van Steirteghem, A. C. (1992). Pregnancies after intracytoplasmic injection of

single spermatozoon into an oocyte. The Lancet, 340(8810), 17-18. Pardo, R., & Calvo, F. (2008). Attitudes toward embryo research, worldviews, and the moral status of the embryo

frame. Science Communication. doi:10.1177/1075547008319432 Pennings, G., de Wert, G., Shenfield, F., Cohen, J., Tarlatzis, B., & Devroey, P. (2007). ESHRE Task Force on Ethics

and Law 13: the welfare of the child in medically assisted reproduction. Human Reproduction, 22(10), 2585-2588. doi:10.1093/humrep/dem237

97

Provoost, V., Tilleman, K., D'Angelo, A., De Sutter, P., de Wert, G., Nelen, W., . . . Dondorp, W. (2014). Beyond the dichotomy: a tool for distinguishing between experimental, innovative and established treatment. Human Reproduction, 29(3), 413-417. doi:10.1093/humrep/det463

Rao, R. (2006). Coercion, commercialization, and commodification: the ethics of compensation for egg donors in stem cell research. Berkeley Tech. LJ, 21, 1055.

Rawls, J. (1971). A Theory of Justice (Cambridge. Mass.: Harvard University. Rawls, J. (1993). Political liberalism: Columbia University Press. Reinders, J. S. (1993). De bescherming van het ongeboren leven: morele en godsdienstige overwegingen bij het

experimenteren met menselijke embryo's: Ten Have. Rowland, R. (1992). Living laboratories: Women and reproductive technologies: Indiana University Press. Sandel, M. J. (2004). Embryo ethics-the moral logic of stem-cell research. New England Journal of Medicine, 351,

207-208. Schippers, E. I. (2016). Kabinetsreactie op het Pallas rapport. (829299-140854-PG). Den Haag. Setti, P. L., Albani, E., Cesana, A., Novara, P., Zannoni, E., Baggiani, A., . . . Scaravelli, G. (2010). Italian Constitutional

Court modifications of a restrictive assisted reproduction technology law significantly improve pregnancy rate. Human Reproduction, deq342.

Sinclair, K., Young, L., Wilmut, I., & McEvoy, T. (2000). In-utero overgrowth in ruminants following embryo culture: lessons from mice and a warning to men. Human Reproduction, 15(suppl 5), 68-86.

Singer, P. (1980). Practical ethics: Cambridge university press. SNU. (2006). Investigation Committee Report. Retrieved from Seoul: Steinbock, B. (2011). Life before birth: the moral and legal status of embryos and fetuses: Oxford University Press. Summers, M., & Racowsky, C. (2008). John D. Biggers a: A conversation with Michael Summers & Catherine

Racowsky. Human Fertility, 11(4), 211-221. Sumner, L. W. (1981). Abortion and moral theory: Princeton University Press. Tachibana, M., Amato, P., Sparman, M., Gutierrez, N. M., Tippner-Hedges, R., Ma, H., . . . Sritanaudomchai, H.

(2013). Human embryonic stem cells derived by somatic cell nuclear transfer. Cell, 153(6), 1228-1238. Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult

fibroblast cultures by defined factors. Cell, 126(4), 663-676. Taylor, C. (1985). Human agency and language. Cambridge: Cambridge University Press. Taylor, C. (1995). The dialogical self. In R. F. Goodman & R. F. Walter (Eds.), Rethinking knowledge: Reflections

across the disciplines (pp. 57-66). Albany: State University of New York Press. Testa, G., & Harris, J. (2004). Ethical aspects of ES cell-derived gametes. Science, 1719-1719. Testa, G., & Harris, J. (2005). Ethics and synthetic gametes. Bioethics, 19(2), 146-166. Thadani, V. M. (1979). Injection of sperm heads into immature rat oocytes. Journal of Experimental Zoology, 210(1),

161-168. Tooley, M. (1983). Abortion and infanticide: Oxford University Press, USA. van Beers, B. (2009). De juridische gestaltes van het menselijk embryo Persoon en lichaam in het recht: menselijke

waardigheid en zelfbeschikking in het tijdperk van de medische biotechnologie: Boom Juridische uitgevers. van Beers, B. (2016, June 2nd 2016). Wijzig de status van het embryo niet buiten het parlement om. de Volkskrant,

p. 22. Retrieved from http://www6.lexisnexis.com/publisher/EndUser?Action=UserDisplayFullDocument&orgId=102575&Em=1&topicId=158330010&docId=l:2596587146&start=6&md5=183a284e7a79ec69ed4d3f82577d5f0&sendDate=20160602

Van Steirteghem, A. (2008). What next for assisted reproductive technology? A plea for an evidence-based approach. Human Reproduction, 23(12), 2615-2616.

Vélez, J. R. (2004). Immediate animation: Thomistic principles applied to Norman Ford's objections. Ethics & medicine: a Christian perspective on issues in bioethics, 21(1), 11-28.

Warren, M. A. (1997). Moral status: Obligations to persons and other living things: Clarendon Press. Yamada, M., Johannesson, B., Sagi, I., Burnett, L. C., Kort, D. H., Prosser, R. W., . . . Greenberg, E. (2014). Human

oocytes reprogram adult somatic nuclei of a type 1 diabetic to diploid pluripotent stem cells. Nature, 510(7506), 533-536.

Yang, S., Bo, J., Hu, H., Guo, X., Tian, R., Sun, C., . . . Zou, S. (2012). Derivation of male germ cells from induced pluripotent stem cells in vitro and in reconstituted seminiferous tubules. Cell proliferation, 45(2), 91-100.

98

Yang, X., Smith, S. L., Tian, X. C., Lewin, H. A., Renard, J.-P., & Wakayama, T. (2007). Nuclear reprogramming of cloned embryos and its implications for therapeutic cloning. Nature genetics, 39(3), 295-302.

Zimmerman, M. J. (2014). Intrinsic vs. Extrinsic Value. Retrieved from The Stanford Encyclopedia of Philosophy website: http://plato.stanford.edu/entries/value-intrinsic-extrinsic/

ZonMw. (2012). Reageerbuisdebat Retrieved from Zoetermeer: